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Xie Y, Wang R, McClatchy DB, Ma Y, Diedrich J, Sanchez-Alavez M, Petrascheck M, Yates JR, Cline HT. Activity-dependent synthesis of Emerin gates neuronal plasticity by regulating proteostasis. Cell Rep 2025; 44:115439. [PMID: 40208794 PMCID: PMC12080591 DOI: 10.1016/j.celrep.2025.115439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 11/26/2024] [Accepted: 02/26/2025] [Indexed: 04/12/2025] Open
Abstract
Neurons dynamically regulate their proteome in response to sensory input, a key process underlying experience-dependent plasticity. We characterized the visual experience-dependent nascent proteome in mice within a brief, defined time window after stimulation using an optimized metabolic labeling approach. Visual experience induced cell-type-specific and age-dependent alterations in the nascent proteome, including proteostasis-related proteins. Emerin is the top activity-induced candidate plasticity protein. Activity-induced neuronal Emerin synthesis is rapid and transcription independent. Emerin broadly inhibits protein synthesis, decreasing translation regulators and synaptic proteins. Decreasing Emerin shifted the dendritic spine population from a predominantly mushroom morphology to filopodia and decreased network connectivity. Blocking visual experience-induced Emerin reduced visually evoked electrophysiological responses and impaired behaviorally assessed visual information processing. Our findings support a proteostatic model in which visual experience-induced Emerin provides a feedforward block on further protein synthesis, refining temporal control of activity-induced plasticity proteins and optimizing visual system function.
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Affiliation(s)
- Yi Xie
- Department of Neuroscience and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Graduate Program, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Ruoxi Wang
- Department of Neuroscience and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Daniel B McClatchy
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Yuanhui Ma
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Jolene Diedrich
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Manuel Sanchez-Alavez
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Michael Petrascheck
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - John R Yates
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Hollis T Cline
- Department of Neuroscience and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
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Yu H, Nishio H, Barbi J, Mitchell-Flack M, Vignali PDA, Zheng Y, Lebid A, Chang KY, Fu J, Higgins M, Huang CT, Zhang X, Li Z, Blosser L, Tam A, Drake C, Pardoll D. Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity. eLife 2024; 13:RP96812. [PMID: 39565188 PMCID: PMC11578584 DOI: 10.7554/elife.96812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2024] Open
Abstract
The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report in mice that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency in mice causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.
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Affiliation(s)
- Hong Yu
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Hiroshi Nishio
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Joseph Barbi
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Marisa Mitchell-Flack
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Paolo DA Vignali
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Ying Zheng
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Andriana Lebid
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Kwang-Yu Chang
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Juan Fu
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Makenzie Higgins
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Ching-Tai Huang
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Xuehong Zhang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical UniversityDalianChina
| | - Zhiguang Li
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical UniversityDalianChina
| | - Lee Blosser
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Ada Tam
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Charles Drake
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Drew Pardoll
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of MedicineBaltimoreUnited States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
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Nolbrant S, Wallace JL, Ding J, Zhu T, Sevetson JL, Kajtez J, Baldacci IA, Corrigan EK, Hoglin K, McMullen R, Schmitz MT, Breevoort A, Swope D, Wu F, Pavlovic BJ, Salama SR, Kirkeby A, Huang H, Schaefer NK, Pollen AA. INTERSPECIES ORGANOIDS REVEAL HUMAN-SPECIFIC MOLECULAR FEATURES OF DOPAMINERGIC NEURON DEVELOPMENT AND VULNERABILITY. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.14.623592. [PMID: 39605599 PMCID: PMC11601475 DOI: 10.1101/2024.11.14.623592] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
The disproportionate expansion of telencephalic structures during human evolution involved tradeoffs that imposed greater connectivity and metabolic demands on midbrain dopaminergic neurons. Despite the central role of dopaminergic neurons in human-enriched disorders, molecular specializations associated with human-specific features and vulnerabilities of the dopaminergic system remain unexplored. Here, we establish a phylogeny-in-a-dish approach to examine gene regulatory evolution by differentiating pools of human, chimpanzee, orangutan, and macaque pluripotent stem cells into ventral midbrain organoids capable of forming long-range projections, spontaneous activity, and dopamine release. We identify human-specific gene expression changes related to axonal transport of mitochondria and reactive oxygen species buffering and candidate cis- and trans-regulatory mechanisms underlying gene expression divergence. Our findings are consistent with a model of evolved neuroprotection in response to tradeoffs related to brain expansion and could contribute to the discovery of therapeutic targets and strategies for treating disorders involving the dopaminergic system.
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Affiliation(s)
- Sara Nolbrant
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
- These authors contributed equally
| | - Jenelle L. Wallace
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
- These authors contributed equally
| | - Jingwen Ding
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
- These authors contributed equally
| | - Tianjia Zhu
- Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
| | - Jess L. Sevetson
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Cruz, CA, United States of America
- Genomics Institute, University of California Santa Cruz, CA, United States of America
| | - Janko Kajtez
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Isabella A. Baldacci
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Emily K. Corrigan
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Kaylynn Hoglin
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Reed McMullen
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Matthew T. Schmitz
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Arnar Breevoort
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Dani Swope
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Fengxia Wu
- Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Anatomy and Neurobiology, Shandong University, Jinan, Shandong Province, China
| | - Bryan J. Pavlovic
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Sofie R. Salama
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Cruz, CA, United States of America
- Genomics Institute, University of California Santa Cruz, CA, United States of America
| | - Agnete Kirkeby
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Experimental Medical Sciences, Wallenberg Center for Molecular Medicine (WCMM) and Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Hao Huang
- Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States
| | - Nathan K. Schaefer
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Alex A. Pollen
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
- Lead contact
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Theofanopoulou C. Tapping into the vocal learning and rhythmic synchronization hypothesis. BMC Neurosci 2024; 25:63. [PMID: 39506690 PMCID: PMC11539701 DOI: 10.1186/s12868-024-00863-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 03/19/2024] [Indexed: 11/08/2024] Open
Abstract
In this article, I present three main points that could benefit the "vocal learning and rhythmic synchronization hypothesis", encompassing neurogenetic mechanisms of gene expression transmission and single motor neuron function, classification of different behavioral motor phenotypes (e.g., spontaneous vs. voluntary), and other evolutionary considerations (i.e., the involvement of reward mechanisms).
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Affiliation(s)
- Constantina Theofanopoulou
- Rockefeller University, New York, NY, USA.
- Center for Ballet and the Arts, New York University, New York, NY, USA.
- Drexel University, Philadelphia, PA, USA.
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5
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Meng P, Zhu L, Guo J, Li Y, Wei Y, Sun J, Zhu J. Preparation of recombinant neuritin protein. Protein Expr Purif 2024; 223:106554. [PMID: 39002828 DOI: 10.1016/j.pep.2024.106554] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 07/15/2024]
Abstract
Neuritin plays an important role in promoting nerve injury repair and maintaining synaptic plasticity, making it a potential therapeutic target for the treatment of nerve injury and neurodegenerative diseases. The present study aimed to obtain an active, unlabeled neuritin protein. Initially, a neuritin protein expression system with an enterokinase site was constructed in Escherichia coli. After optimizing induction conditions and screening for high expression, a neuritin recombinant protein with purity exceeding 85 % was obtained through Ni-affinity chromatography. Subsequently, unlabeled neuritin with a molecular weight of 11 kDa was obtained through the enzymatic cleavage of the His label using an enterokinase. Furthermore, a neuritin recombinant protein with purity exceeding 95 % was obtained using gel chromatography. Functional investigations revealed that neurite outgrowth of PC12 cells was stimulated by the isolated neuritin. This study establishes a method to obtain active and unlabeled neuritin protein, providing a foundation for subsequent research on its biological functions.
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Affiliation(s)
- Pingping Meng
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
| | - Liyan Zhu
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
| | - Jiatong Guo
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
| | - Yuanyuan Li
- Shawan City People's Hospital, Shawan, Xinjiang, 832100, China
| | - Yu Wei
- The First Affiliated Hospital of Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
| | - Jiawei Sun
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
| | - Jingling Zhu
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China.
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Hameed SS, Bodi NE, Miller RC, Sharma TP. Neuritin 1 Drives Therapeutic Preservation of Retinal Ganglion Cells in an Ex Vivo Human Glaucoma Model. J Ocul Pharmacol Ther 2024; 40:596-607. [PMID: 38995841 PMCID: PMC11698685 DOI: 10.1089/jop.2024.0041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 06/10/2024] [Indexed: 07/14/2024] Open
Abstract
Purpose: Glaucoma is a leading cause of irreversible blindness. Glaucomatous intraocular pressure (IOP) triggers deleterious effects, including gliosis, optic nerve (ON) axonal retraction, neurotrophic factor deprivation, inflammation, and other pathological events, leading to retinal ganglion cell (RGC) loss. Trophic factor impairment enhances RGC apoptosis susceptibility. Neuritin 1 (NRN1), a neurotrophic protein downstream of various neurotrophins, exhibited RGC protection and regeneration in axotomy models. We evaluated human recombinant NRN1's impact on human RGCs cultured in pressurized conditions within the ex vivo translaminar autonomous system to simulate glaucoma pathogenesis. Methods: Human glaucomatous and non-glaucomatous donor eyes were obtained from eye banks according to the Declaration of Helsinki. Initially, we evaluated NRN1and RGC marker expression in glaucoma and non-glaucomatous retina to determine the NRN1 level and its association with RGC loss. Further, we evaluated NRN1's therapeutic potential by treating pressurized human eyes at normal and high IOP for seven days. Retina, ON, and conditioned medium were analyzed for RGC survival (THY1, RBPMS), gliosis (GFAP), apoptosis (CASP3, CASP7), and extracellular matrix deposition (COLIV, FN) by qRT-PCR and western blotting. Paraphenylenediamine staining assessed ON axonal degeneration, whereas ex vivo electroretinogram assessed retinal activity. Results: Glaucomatous retinas exhibited significant reductions in both NRN1 (*p = 0.007, n = 5) and RGC marker expression (*p = 0.04, n = 5). NRN1 treatment reduced gliosis, extracellular matrix deposition, ON degeneration, and increased retinal activity in pressure-perfused eyes. Conclusions: Our study confirms that NRN1 enhances human RGC survival and improves retinal function in degenerative conditions, substantiating it as a promising candidate for rescuing human RGCs from degeneration.
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Affiliation(s)
- Shahna S. Hameed
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Nicole E. Bodi
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ryan C. Miller
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Tasneem P. Sharma
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana
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Shimada T, Kohyama K, Yoshida T, Yamagata K. Neuritin Controls Axonal Branching in Serotonin Neurons: A Possible Mediator Involved in the Regulation of Depressive and Anxiety Behaviors via FGF Signaling. J Neurosci 2024; 44:e0129232024. [PMID: 39197941 PMCID: PMC11466069 DOI: 10.1523/jneurosci.0129-23.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/01/2024] Open
Abstract
Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, are thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knock-out (KO) mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin KO mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of neuritin was decreased by unpredictable chronic stress in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves fibroblast growth factor (FGF) signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro. Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior.
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Affiliation(s)
- Tadayuki Shimada
- Child Brain Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan
| | - Kuniko Kohyama
- Child Brain Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan
| | - Tomoyuki Yoshida
- Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan
| | - Kanato Yamagata
- Child Brain Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan
- Department of Psychiatry, Takada Nishishiro Hospital, Joetsu, Niigata 943-0834, Japan
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8
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Yu H, Nishio H, Barbi J, Mitchell-Flack M, Vignali PDA, Zheng Y, Lebid A, Chang KY, Fu J, Higgins M, Huang CT, Zhang X, Li Z, Blosser L, Tam A, Drake CG, Pardoll DM. Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.31.578284. [PMID: 38352414 PMCID: PMC10862906 DOI: 10.1101/2024.01.31.578284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/24/2024]
Abstract
The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.
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Affiliation(s)
- Hong Yu
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hiroshi Nishio
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Current address: Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Joseph Barbi
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Current address: Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY14263, USA
| | - Marisa Mitchell-Flack
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Paolo D A Vignali
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Current address: University of Pittsburgh, Carnegie Mellon
| | - Ying Zheng
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andriana Lebid
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kwang-Yu Chang
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Current address: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Juan Fu
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Makenzie Higgins
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ching-Tai Huang
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Current address: Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, Taiwan
| | - Xuehong Zhang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian 116044, China
| | - Zhiguang Li
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian 116044, China
| | - Lee Blosser
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ada Tam
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Charles G Drake
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Current address: Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032
| | - Drew M Pardoll
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Xie Y, Wang R, McClatchy DB, Ma Y, Diedrich J, Sanchez-Alavez M, Petrascheck M, Yates JR, Cline HT. Activity-dependent synthesis of Emerin gates neuronal plasticity by regulating proteostasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.30.600712. [PMID: 38979362 PMCID: PMC11230442 DOI: 10.1101/2024.06.30.600712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Neurons dynamically regulate their proteome in response to sensory input, a key process underlying experience-dependent plasticity. We characterized the visual experience-dependent nascent proteome within a brief, defined time window after stimulation using an optimized metabolic labeling approach. Visual experience induced cell type-specific and age-dependent alterations in the nascent proteome, including proteostasis-related processes. We identified Emerin as the top activity-induced candidate plasticity protein and demonstrated that its rapid activity-induced synthesis is transcription-independent. In contrast to its nuclear localization and function in myocytes, activity-induced neuronal Emerin is abundant in the endoplasmic reticulum and broadly inhibits protein synthesis, including translation regulators and synaptic proteins. Downregulating Emerin shifted the dendritic spine population from predominantly mushroom morphology to filopodia and decreased network connectivity. In mice, decreased Emerin reduced visual response magnitude and impaired visual information processing. Our findings support an experience-dependent feed-forward role for Emerin in temporally gating neuronal plasticity by negatively regulating translation.
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10
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Devitt L, Westphal D, Pieger K, Schneider N, Bosserhoff AK, Kuphal S. NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma. Cell Commun Signal 2024; 22:256. [PMID: 38705997 PMCID: PMC11071257 DOI: 10.1186/s12964-024-01632-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 04/24/2024] [Indexed: 05/07/2024] Open
Abstract
BACKGROUND Melanoma is a highly heterogeneous cancer, in which frequent changes in activation of signaling pathways lead to a high adaptability to ever changing tumor microenvironments. The elucidation of cancer specific signaling pathways is of great importance, as demonstrated by the inhibitor of the common BrafV600E mutation PLX4032 in melanoma treatment. We therefore investigated signaling pathways that were influenced by neurotrophin NRN1, which has been shown to be upregulated in melanoma. METHODS Using a cell culture model system with an NRN1 overexpression, we investigated the influence of NRN1 on melanoma cells' functionality and signaling. We employed real time cell analysis and spheroid formation assays, while for investigation of molecular mechanisms we used a kinase phosphorylation kit as well as promotor activity analysis followed by mRNA and protein analysis. RESULTS We revealed that NRN1 interacts directly with the cleaved intracellular domain (NICD) of Notch1 and Notch3, causing a potential retention of NICD in the cytoplasm and thereby reducing the expression of its direct downstream target Hes1. This leads to decreased sequestration of JAK and STAT3 in a Hes1-driven phosphorylation complex. Consequently, our data shows less phosphorylation of STAT3 while presenting an accumulation of total protein levels of STAT3 in association with NRN1 overexpression. The potential of the STAT3 signaling pathway to act in both a tumor suppressive and oncogenic manner led us to investigate specific downstream targets - namely Vegf A, Mdr1, cMet - which were found to be upregulated under oncogenic levels of NRN1. CONCLUSIONS In summary, we were able to show that NRN1 links oncogenic signaling events between Notch and STAT3 in melanoma. We also suggest that in future research more attention should be payed to cellular regulation of signaling molecules outside of the classically known phosphorylation events.
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Affiliation(s)
- Lucia Devitt
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Dana Westphal
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT) Dresden, a partnership between German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Katharina Pieger
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Nadja Schneider
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Anja Katrin Bosserhoff
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Silke Kuphal
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany.
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11
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Pavon N, Diep K, Yang F, Sebastian R, Martinez-Martin B, Ranjan R, Sun Y, Pak C. Patterning ganglionic eminences in developing human brain organoids using a morphogen-gradient-inducing device. CELL REPORTS METHODS 2024; 4:100689. [PMID: 38228151 PMCID: PMC10831957 DOI: 10.1016/j.crmeth.2023.100689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/21/2023] [Accepted: 12/18/2023] [Indexed: 01/18/2024]
Abstract
In early neurodevelopment, the central nervous system is established through the coordination of various neural organizers directing tissue patterning and cell differentiation. Better recapitulation of morphogen gradient production and signaling will be crucial for establishing improved developmental models of the brain in vitro. Here, we developed a method by assembling polydimethylsiloxane devices capable of generating a sustained chemical gradient to produce patterned brain organoids, which we termed morphogen-gradient-induced brain organoids (MIBOs). At 3.5 weeks, MIBOs replicated dorsal-ventral patterning observed in the ganglionic eminences (GE). Analysis of mature MIBOs through single-cell RNA sequencing revealed distinct dorsal GE-derived CALB2+ interneurons, medium spiny neurons, and medial GE-derived cell types. Finally, we demonstrate long-term culturing capabilities with MIBOs maintaining stable neural activity in cultures grown up to 5.5 months. MIBOs demonstrate a versatile approach for generating spatially patterned brain organoids for embryonic development and disease modeling.
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Affiliation(s)
- Narciso Pavon
- Graduate Program in Neuroscience and Behavior, UMass Amherst, Amherst, MA 01003, USA; Department of Biochemistry and Molecular Biology, UMass Amherst, Amherst, MA 01003, USA
| | - Karmen Diep
- Department of Biochemistry and Molecular Biology, UMass Amherst, Amherst, MA 01003, USA
| | - Feiyu Yang
- Department of Mechanical and Industrial Engineering, UMass Amherst, Amherst, MA 01003, USA
| | - Rebecca Sebastian
- Graduate Program in Neuroscience and Behavior, UMass Amherst, Amherst, MA 01003, USA; Department of Biochemistry and Molecular Biology, UMass Amherst, Amherst, MA 01003, USA
| | - Beatriz Martinez-Martin
- Department of Biochemistry and Molecular Biology, UMass Amherst, Amherst, MA 01003, USA; Graduate Program in Molecular and Cellular Biology, UMass Amherst, Amherst, MA 01003, USA
| | - Ravi Ranjan
- Genomics Core, Institute of Applied Life Sciences, UMass Amherst, Amherst, MA 01003, USA
| | - Yubing Sun
- Department of Mechanical and Industrial Engineering, UMass Amherst, Amherst, MA 01003, USA.
| | - ChangHui Pak
- Department of Biochemistry and Molecular Biology, UMass Amherst, Amherst, MA 01003, USA.
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12
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Xu H, Dong J, Li Y, Zhang L, Yin J, Zhu C, Wang X, Ren K, Zhang H, Zhao D. Neuritin has a neuroprotective role in the rat model of acute ischemia stroke by inhibiting neuronal apoptosis and NLRP3 inflammasome. J Stroke Cerebrovasc Dis 2023; 32:107391. [PMID: 37832268 DOI: 10.1016/j.jstrokecerebrovasdis.2023.107391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 09/22/2023] [Accepted: 09/24/2023] [Indexed: 10/15/2023] Open
Abstract
OBJECTIVES This study explored the anti-inflammatory, anti-neuronal apoptosis, and neuroprotective effects of Neuritin in rat models of acute ischemia stroke (AIS). METHODS AIS was induced in male Sprague Dawley rats by middle cerebral artery occlusion (MCAO). Rats were divided into sham, MCAO, MCAO+neuritin, MCAO + neuritin + PBS, MCAO + neuritin+MCC950, and MCAO + neuritin + MSU groups. Neurological score assessment, brain water content measurement, HE staining, TTC staining, TUNEL staining, ELISA, and Western blot were performed. RESULTS Neuritin significantly improved the neurobehavioral score, infarct size, brain water content, apoptosis, and neuroinflammatory response compared with the MCAO and MCAO + PBS groups within 24 h after AIS. Moreover, Neuritin inhibited the protein expression of NLRP3 inflammasome, and reduced the expression of IL-18 and IL-1B, thereby reducing the inflammatory response. Meanwhile, the neuroprotection, anti-inflammation, and anti-apoptosis effects of Neuritin were enhanced by MCC950 but partly counteracted by MSU. CONCLUSION Neuritin may reduce brain injury after AIS by inhibiting the expression of NLRP3 inflammasome and then inhibiting the inflammatory response.
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Affiliation(s)
- Hui Xu
- Department of Neurosurgery, the First Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Jiangtao Dong
- Department of Neurosurgery, the First Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Yang Li
- Department of Neurosurgery, the First Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Lei Zhang
- Department of Neuromedicine, Beitun Hospital, the Tenth Division of Xinjiang Production and Construction Corps, Beitun 836000, China
| | - Jiangwen Yin
- Department of Anesthesiology, First Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Chao Zhu
- Department of Neurosurgery, the First Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Xu Wang
- Department of Neurosurgery, the First Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Kunhao Ren
- Department of Neurosurgery, the First Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Hao Zhang
- Department of Neurosurgery, the First Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Dong Zhao
- Department of Neurosurgery, the First Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China.
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13
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Roethler O, Zohar E, Cohen-Kashi Malina K, Bitan L, Gabel HW, Spiegel I. Single genomic enhancers drive experience-dependent GABAergic plasticity to maintain sensory processing in the adult cortex. Neuron 2023; 111:2693-2708.e8. [PMID: 37354902 DOI: 10.1016/j.neuron.2023.05.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 03/29/2023] [Accepted: 05/30/2023] [Indexed: 06/26/2023]
Abstract
Experience-dependent plasticity of synapses modulates information processing in neural circuits and is essential for cognitive functions. The genome, via non-coding enhancers, was proposed to control information processing and circuit plasticity by regulating experience-induced transcription of genes that modulate specific sets of synapses. To test this idea, we analyze here the cellular and circuit functions of the genomic mechanisms that control the experience-induced transcription of Igf1 (insulin-like growth factor 1) in vasoactive intestinal peptide (VIP) interneurons (INs) in the visual cortex of adult mice. We find that two sensory-induced enhancers selectively and cooperatively drive the activity-induced transcription of Igf1 to thereby promote GABAergic inputs onto VIP INs and to homeostatically control the ratio between excitation and inhibition (E/I ratio)-in turn, this restricts neural activity in VIP INs and principal excitatory neurons and maintains spatial frequency tuning. Thus, enhancer-mediated activity-induced transcription maintains sensory processing in the adult cortex via homeostatic modulation of E/I ratio.
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Affiliation(s)
- Ori Roethler
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
| | - Eran Zohar
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
| | - Katayun Cohen-Kashi Malina
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
| | - Lidor Bitan
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Harrison Wren Gabel
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
| | - Ivo Spiegel
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel.
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14
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Boudkkazi S, Schwenk J, Nakaya N, Brechet A, Kollewe A, Harada H, Bildl W, Kulik A, Dong L, Sultana A, Zolles G, Schulte U, Tomarev S, Fakler B. A Noelin-organized extracellular network of proteins required for constitutive and context-dependent anchoring of AMPA-receptors. Neuron 2023; 111:2544-2556.e9. [PMID: 37591201 PMCID: PMC10441612 DOI: 10.1016/j.neuron.2023.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 04/21/2023] [Accepted: 07/20/2023] [Indexed: 08/19/2023]
Abstract
Information processing and storage in the brain rely on AMPA-receptors (AMPARs) and their context-dependent dynamics in synapses and extra-synaptic sites. We found that distribution and dynamics of AMPARs in the plasma membrane are controlled by Noelins, a three-member family of conserved secreted proteins expressed throughout the brain in a cell-type-specific manner. Noelin tetramers tightly assemble with the extracellular domains of AMPARs and interconnect them in a network-like configuration with a variety of secreted and membrane-anchored proteins including Neurexin1, Neuritin1, and Seizure 6-like. Knock out of Noelins1-3 profoundly reduced AMPARs in synapses onto excitatory and inhibitory (inter)neurons, decreased their density and clustering in dendrites, and abolished activity-dependent synaptic plasticity. Our results uncover an endogenous mechanism for extracellular anchoring of AMPARs and establish Noelin-organized networks as versatile determinants of constitutive and context-dependent neurotransmission.
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Affiliation(s)
- Sami Boudkkazi
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany
| | - Jochen Schwenk
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany
| | - Naoki Nakaya
- National Eye Institute, Section of Retinal Ganglion Cell Biology, National Institutes of Health, Bethesda, MD, USA
| | - Aline Brechet
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany
| | - Astrid Kollewe
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany
| | - Harumi Harada
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany
| | - Wolfgang Bildl
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany
| | - Akos Kulik
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany
| | - Lijin Dong
- National Eye Institute, Genetic Engineering Facility, National Institutes of Health, Bethesda, MD, USA
| | - Afia Sultana
- National Eye Institute, Section of Retinal Ganglion Cell Biology, National Institutes of Health, Bethesda, MD, USA
| | - Gerd Zolles
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany
| | - Uwe Schulte
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany; Signaling Research Centers BIOSS and CIBSS, University of Freiburg, Schänzlestr. 18, 79104 Freiburg, Germany; Logopharm GmbH, Schlossstr. 14, 79232 March-Buchheim, Germany
| | - Stanislav Tomarev
- National Eye Institute, Section of Retinal Ganglion Cell Biology, National Institutes of Health, Bethesda, MD, USA.
| | - Bernd Fakler
- Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, 79104 Freiburg, Germany; Signaling Research Centers BIOSS and CIBSS, University of Freiburg, Schänzlestr. 18, 79104 Freiburg, Germany.
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15
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Hurst C, Pugh DA, Abreha MH, Duong DM, Dammer EB, Bennett DA, Herskowitz JH, Seyfried NT. Integrated Proteomics to Understand the Role of Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer's Disease. Mol Cell Proteomics 2023; 22:100542. [PMID: 37024090 PMCID: PMC10233303 DOI: 10.1016/j.mcpro.2023.100542] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 03/16/2023] [Accepted: 03/28/2023] [Indexed: 04/08/2023] Open
Abstract
The molecular mechanisms and pathways enabling certain individuals to remain cognitively normal despite high levels of Alzheimer's disease (AD) pathology remain incompletely understood. These cognitively normal people with AD pathology are described as preclinical or asymptomatic AD (AsymAD) and appear to exhibit cognitive resilience to the clinical manifestations of AD dementia. Here we present a comprehensive network-based approach from cases clinically and pathologically defined as asymptomatic AD to map resilience-associated pathways and extend mechanistic validation. Multiplex tandem mass tag MS (TMT-MS) proteomic data (n = 7787 proteins) was generated on brain tissue from Brodmann area 6 and Brodmann area 37 (n = 109 cases, n = 218 total samples) and evaluated by consensus weighted gene correlation network analysis. Notably, neuritin (NRN1), a neurotrophic factor previously linked to cognitive resilience, was identified as a hub protein in a module associated with synaptic biology. To validate the function of NRN1 with regard to the neurobiology of AD, we conducted microscopy and physiology experiments in a cellular model of AD. NRN1 provided dendritic spine resilience against amyloid-β (Aβ) and blocked Aβ-induced neuronal hyperexcitability in cultured neurons. To better understand the molecular mechanisms of resilience to Aβ provided by NRN1, we assessed how exogenous NRN1 alters the proteome by TMT-MS (n = 8238 proteins) of cultured neurons and integrated the results with the AD brain network. This revealed overlapping synapse-related biology that linked NRN1-induced changes in cultured neurons with human pathways associated with cognitive resilience. Collectively, this highlights the utility of integrating the proteome from the human brain and model systems to advance our understanding of resilience-promoting mechanisms and prioritize therapeutic targets that mediate resilience to AD.
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Affiliation(s)
- Cheyenne Hurst
- Department of Biochemistry, Emory School of Medicine, Emory Goizueta Alzheimer's Disease Research Center, Atlanta, Georgia, USA
| | - Derian A Pugh
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| | - Measho H Abreha
- Department of Biochemistry, Emory School of Medicine, Emory Goizueta Alzheimer's Disease Research Center, Atlanta, Georgia, USA
| | - Duc M Duong
- Department of Biochemistry, Emory School of Medicine, Emory Goizueta Alzheimer's Disease Research Center, Atlanta, Georgia, USA
| | - Eric B Dammer
- Department of Biochemistry, Emory School of Medicine, Emory Goizueta Alzheimer's Disease Research Center, Atlanta, Georgia, USA
| | - David A Bennett
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
| | - Jeremy H Herskowitz
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
| | - Nicholas T Seyfried
- Department of Biochemistry, Emory School of Medicine, Emory Goizueta Alzheimer's Disease Research Center, Atlanta, Georgia, USA.
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16
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Papadogianni G, Ravens I, Hassan A, Flatley A, Feederle R, Bernhardt G, Georgiev H. Establishment and Functional Characterization of Murine Monoclonal Antibodies Recognizing Neuritin. Antibodies (Basel) 2023; 12:antib12020028. [PMID: 37092449 PMCID: PMC10123642 DOI: 10.3390/antib12020028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/17/2023] [Accepted: 03/30/2023] [Indexed: 04/25/2023] Open
Abstract
Neuritin represents a neurotrophic factor that is not only important in neuronal development and plasticity but also impacts endothelial angiogenesis, cell migration, tumor growth and the production of antibodies by B cells. We established monoclonal mouse anti-mouse neuritin antibodies by immunizing knock-out mice with two different neuritin-derived peptides. Because neuritin is well conserved between species, these new monoclonal antibodies recognize the neuritin of a wide variety of species, including human. Moreover, they not only recognize specifically surface-bound neuritin expressed by murine follicular regulatory T cells but also the block binding of recombinant neuritin to germinal center B cells. This suggests that these newly generated tools will be of great use in studying neuritin expression and function.
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Affiliation(s)
| | - Inga Ravens
- Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
| | - Ahmed Hassan
- Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
| | - Andrew Flatley
- Monoclonal Antibody Core Facility, Helmholtz Center Munich, Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany
| | - Regina Feederle
- Monoclonal Antibody Core Facility, Helmholtz Center Munich, Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany
| | - Günter Bernhardt
- Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
| | - Hristo Georgiev
- Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
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17
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Garone MG, Birsa N, Rosito M, Salaris F, Mochi M, de Turris V, Nair RR, Cunningham TJ, Fisher EMC, Morlando M, Fratta P, Rosa A. ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity. Commun Biol 2021; 4:1025. [PMID: 34471224 PMCID: PMC8410767 DOI: 10.1038/s42003-021-02538-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 08/10/2021] [Indexed: 12/13/2022] Open
Abstract
Mutations in the RNA-binding protein (RBP) FUS have been genetically associated with the motoneuron disease amyotrophic lateral sclerosis (ALS). Using both human induced pluripotent stem cells and mouse models, we found that FUS-ALS causative mutations affect the activity of two relevant RBPs with important roles in neuronal RNA metabolism: HuD/ELAVL4 and FMRP. Mechanistically, mutant FUS leads to upregulation of HuD protein levels through competition with FMRP for HuD mRNA 3'UTR binding. In turn, increased HuD levels overly stabilize the transcript levels of its targets, NRN1 and GAP43. As a consequence, mutant FUS motoneurons show increased axon branching and growth upon injury, which could be rescued by dampening NRN1 levels. Since similar phenotypes have been previously described in SOD1 and TDP-43 mutant models, increased axonal growth and branching might represent broad early events in the pathogenesis of ALS.
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Affiliation(s)
- Maria Giovanna Garone
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Nicol Birsa
- UCL Queen Square Institute of Neurology, University College London, London, UK
- UK Dementia Research Institute, University College London, London, UK
| | - Maria Rosito
- Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy
| | - Federico Salaris
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
- Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy
| | - Michela Mochi
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Valeria de Turris
- Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy
| | | | | | | | - Mariangela Morlando
- Department of Pharmaceutical Sciences, "Department of Excellence 2018-2022", University of Perugia, Perugia, Italy
| | - Pietro Fratta
- UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Alessandro Rosa
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy.
- Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy.
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy.
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18
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Gonzalez-Figueroa P, Roco JA, Papa I, Núñez Villacís L, Stanley M, Linterman MA, Dent A, Canete PF, Vinuesa CG. Follicular regulatory T cells produce neuritin to regulate B cells. Cell 2021; 184:1775-1789.e19. [PMID: 33711260 DOI: 10.1016/j.cell.2021.02.027] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/25/2021] [Accepted: 02/08/2021] [Indexed: 10/21/2022]
Abstract
Regulatory T cells prevent the emergence of autoantibodies and excessive IgE, but the precise mechanisms are unclear. Here, we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) cells, produce abundant neuritin protein that targets B cells. Mice lacking Tfr cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased plasma IgE and IgG1. We show that neuritin is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching. Neuritin reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1, and upregulated BCL6. Administration of neuritin to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of neuritin by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies.
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Affiliation(s)
- Paula Gonzalez-Figueroa
- Dept of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Jonathan A Roco
- Dept of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Ilenia Papa
- Dept of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Lorena Núñez Villacís
- Dept of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Maurice Stanley
- Dept of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Michelle A Linterman
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK
| | - Alexander Dent
- Dept of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Pablo F Canete
- Dept of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Carola G Vinuesa
- Dept of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
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Nourbakhsh K, Yadav S. Kinase Signaling in Dendritic Development and Disease. Front Cell Neurosci 2021; 15:624648. [PMID: 33642997 PMCID: PMC7902504 DOI: 10.3389/fncel.2021.624648] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/06/2021] [Indexed: 01/19/2023] Open
Abstract
Dendrites undergo extensive growth and remodeling during their lifetime. Specification of neurites into dendrites is followed by their arborization, maturation, and functional integration into synaptic networks. Each of these distinct developmental processes is spatially and temporally controlled in an exquisite fashion. Protein kinases through their highly specific substrate phosphorylation regulate dendritic growth and plasticity. Perturbation of kinase function results in aberrant dendritic growth and synaptic function. Not surprisingly, kinase dysfunction is strongly associated with neurodevelopmental and psychiatric disorders. Herein, we review, (a) key kinase pathways that regulate dendrite structure, function and plasticity, (b) how aberrant kinase signaling contributes to dendritic dysfunction in neurological disorders and (c) emergent technologies that can be applied to dissect the role of protein kinases in dendritic structure and function.
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Affiliation(s)
| | - Smita Yadav
- Department of Pharmacology, University of Washington, Seattle, WA, United States
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20
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Neuritin-overexpressing transgenic mice demonstrate enhanced neuroregeneration capacity and improved spatial learning and memory recovery after ischemia-reperfusion injury. Aging (Albany NY) 2020; 13:2681-2699. [PMID: 33323541 PMCID: PMC7880330 DOI: 10.18632/aging.202318] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 10/01/2020] [Indexed: 02/01/2023]
Abstract
Acute ischemia-reperfusion (IR)-induced brain injury is further exacerbated by a series of slower secondary pathogenic events, including delayed apoptosis due to neurotrophic factor deficiency. Neuritin, a neurotrophic factor regulating nervous system development and plasticity, is a potential therapeutic target for treatment of IR injury. In this study, Neuritin-overexpressing transgenic (Tg) mice were produced by pronuclear injection and offspring with high overexpression used to generate a line with stable inheritance for testing the neuroprotective capacity of Neuritin against transient global ischemia (TGI). Compared to wild-type mice, transgenic mice demonstrated reduced degradation of the DNA repair factor poly [ADP-ribose] polymerase 1 (PARP 1) in the hippocampus, indicating decreased hippocampal apoptosis rate, and a greater number of surviving hippocampal neurons during the first week post-TGI. In addition, Tg mice showed increased expression of the regeneration markers NF-200, synaptophysin, and GAP-43, and improved recovery of spatial learning and memory. Our findings exhibited that the window of opportunity of neural recovery in Neuritin transgenic mice group had a tendency to move ahead after TGI, which indicated that Neuritin can be used as a potential new therapeutic strategy for improving the outcome of cerebral ischemia injury.
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21
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CPG15/Neuritin Mimics Experience in Selecting Excitatory Synapses for Stabilization by Facilitating PSD95 Recruitment. Cell Rep 2020; 28:1584-1595.e5. [PMID: 31390571 PMCID: PMC6740334 DOI: 10.1016/j.celrep.2019.07.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 06/11/2019] [Accepted: 07/02/2019] [Indexed: 11/24/2022] Open
Abstract
A key feature of brain plasticity is the experience-dependent selection of optimal connections· implemented by a set of activity-regulated genes that dynamically adjust synapse strength and number. The activity-regulated gene cpg15/neuritin has been previously implicated in stabilization and maturation of excitatory synapses. Here· we combine two-photon microscopy with genetic and sensory manipulations to dissect excitatory synapse formation in vivo and examine the role of activity and CPG15 in dendritic spine formation, PSD95 recruitment, and synapse stabilization. We find that neither visual experience nor CPG15 is required for spine formation. However, PSD95 recruitment to nascent spines and their subsequent stabilization requires both. Further, cell-autonomous CPG15 expression is sufficient to replace experience in facilitating PSD95 recruitment and spine stabilization. CPG15 directly interacts with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on immature dendritic spines, suggesting a signaling mode for this small extracellular molecule acting as an experience-dependent “selector” for spine stabilization and synapse maturation. Experience plays a key role in formation and continuous optimization of brain circuits. Subramanian et al. show that the molecule CPG15/neuritin can replace experience in selecting which nascent contacts between neurons are retained, facilitating the recruitment of proteins that promote synapse maturation and stabilization.
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22
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Experience-Dependent Development of Dendritic Arbors in Mouse Visual Cortex. J Neurosci 2020; 40:6536-6556. [PMID: 32669356 DOI: 10.1523/jneurosci.2910-19.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 06/26/2020] [Accepted: 06/30/2020] [Indexed: 12/27/2022] Open
Abstract
The dendritic arbor of neurons constrains the pool of available synaptic partners and influences the electrical integration of synaptic currents. Despite these critical functions, our knowledge of the dendritic structure of cortical neurons during early postnatal development and how these dendritic structures are modified by visual experience is incomplete. Here, we present a large-scale dataset of 849 3D reconstructions of the basal arbor of pyramidal neurons collected across early postnatal development in visual cortex of mice of either sex. We found that the basal arbor grew substantially between postnatal day 7 (P7) and P30, undergoing a 45% increase in total length. However, the gross number of primary neurites and dendritic segments was largely determined by P7. Growth from P7 to P30 occurred primarily through extension of dendritic segments. Surprisingly, comparisons of dark-reared and typically reared mice revealed that a net gain of only 15% arbor length could be attributed to visual experience; most growth was independent of experience. To examine molecular contributions, we characterized the role of the activity-regulated small GTPase Rem2 in both arbor development and the maintenance of established basal arbors. We showed that Rem2 is an experience-dependent negative regulator of dendritic segment number during the visual critical period. Acute deletion of Rem2 reduced directionality of dendritic arbors. The data presented here establish a highly detailed, quantitative analysis of basal arbor development that we believe has high utility both in understanding circuit development as well as providing a framework for computationalists wishing to generate anatomically accurate neuronal models.SIGNIFICANCE STATEMENT Dendrites are the sites of the synaptic connections among neurons. Despite their importance for neural circuit function, only a little is known about the postnatal development of dendritic arbors of cortical pyramidal neurons and the influence of experience. Here we show that the number of primary basal dendritic arbors is already established before eye opening, and that these arbors primarily grow through lengthening of dendritic segments and not through addition of dendritic segments. Surprisingly, visual experience has a modest net impact on overall arbor length (15%). Experiments in KO animals revealed that the gene Rem2 is positive regulator of dendritic length and a negative regulator of dendritic segments.
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Huang T, Li H, Zhang S, Liu F, Wang D, Xu J. Nrn1 Overexpression Attenuates Retinal Ganglion Cell Apoptosis, Promotes Axonal Regeneration, and Improves Visual Function Following Optic Nerve Crush in Rats. J Mol Neurosci 2020; 71:66-79. [DOI: 10.1007/s12031-020-01627-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 06/08/2020] [Indexed: 12/20/2022]
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Song D, Li G, Hong Y, Zhang P, Zhu J, Yang L, Huang J. miR‑199a decreases Neuritin expression involved in the development of Alzheimer's disease in APP/PS1 mice. Int J Mol Med 2020; 46:384-396. [PMID: 32626916 PMCID: PMC7255456 DOI: 10.3892/ijmm.2020.4602] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 04/23/2020] [Indexed: 01/16/2023] Open
Abstract
Neuritin plays an important role in neural development and plasticity. A recent study demonstrated that increasing Neuritin levels attenuated synaptic damage in mice with Alzheimer's disease (AD), which exhibit a decreased Neuritin expression. However, it remains unclear as to whether Neuritin expression is regulated by microRNAs (miRNAs or miRs) in AD. In the present study, it was found that miR-199a decreased Neuritin expression and was therefore involved in the development of AD. Subsequently, differentially expressed miRNAs in AD from datasets and the literature were recruited, and those that could bind Neuritin were predicted using bioinformatics analysis. The present study then focused on the candidate miRNAs that were highly associated with Neuritin and were upregulated in AD. The expression patterns of the candidate miRNAs and Neuritin in the hippocampus and cortex of APP/PS1 (AD model) mice at different stages were then detected and analyzed. It was found that miR-199a expression was significantly increased in the early stages of AD and was negatively associated with Neuritin expression. Furthermore, it was revealed that the decreased Neuritin expression was due to the direct targeting of the Neuritin 3′-UTR by miR-199a. Finally, the association between the spatial memory capacity of APP/PS1 mice and the changes in miR-199a and Neuritin expression protein was investigated. On the whole, the data of the present study suggest that miR-199a is involved in the development of AD by regulating Neuritin expression.
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Affiliation(s)
- Dandan Song
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Guoxiang Li
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Yu Hong
- Department of Prevention Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, P.R. China
| | - Pan Zhang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Jingling Zhu
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Lei Yang
- Department of Prevention Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, P.R. China
| | - Jin Huang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
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Decreased cpg15 augments oxidative stress in sleep deprived mouse brain. Biochem Biophys Res Commun 2019; 522:749-756. [PMID: 31787230 DOI: 10.1016/j.bbrc.2019.11.132] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 11/20/2019] [Indexed: 11/21/2022]
Abstract
Sleep deprivation (SD) has detrimental effects on the physiological function of the brain. However, the underlying mechanism remains elusive. In the present study, we investigated the expression of candidate plasticity-related gene 15 (cpg15), a neurotrophic gene, and its potential role in SD using a REM-SD mouse model. Immunofluorescent and Western blot analysis revealed that the expression of cpg15 protein decreased in the hippocampus, ventral group of the dorsal thalamus (VENT), and somatosensory area of cerebral cortex (SSP) after 24-72 h of REM-SD, and the oxidative stress in these brain regions was increased in parallel, as indicated by the ratio of glutathione (GSH) to its oxidative product (GSSG). Over-expression of cpg15 in thalamus, hippocampus, and cerebral cortex mediated by AAV reduced the oxidative stress in these regions, indicating that the decrease of cpg15 might be a cause that augments oxidative stress in the sleep deprived mouse brain. Collectively, the results imply that cpg15 may play a protective function in the SD-subjected mouse brain via an anti-oxidative function. To our knowledge, this is the first time to provide evidences in the role of cpg15 against SD-induced oxidative stress in the brain.
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26
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Bissen D, Foss F, Acker-Palmer A. AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking. Cell Mol Life Sci 2019; 76:2133-2169. [PMID: 30937469 PMCID: PMC6502786 DOI: 10.1007/s00018-019-03068-7] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 02/12/2019] [Accepted: 03/07/2019] [Indexed: 12/12/2022]
Abstract
To correctly transfer information, neuronal networks need to continuously adjust their synaptic strength to extrinsic stimuli. This ability, termed synaptic plasticity, is at the heart of their function and is, thus, tightly regulated. In glutamatergic neurons, synaptic strength is controlled by the number and function of AMPA receptors at the postsynapse, which mediate most of the fast excitatory transmission in the central nervous system. Their trafficking to, at, and from the synapse, is, therefore, a key mechanism underlying synaptic plasticity. Intensive research over the last 20 years has revealed the increasing importance of interacting proteins, which accompany AMPA receptors throughout their lifetime and help to refine the temporal and spatial modulation of their trafficking and function. In this review, we discuss the current knowledge about the roles of key partners in regulating AMPA receptor trafficking and focus especially on the movement between the intracellular, extrasynaptic, and synaptic pools. We examine their involvement not only in basal synaptic function, but also in Hebbian and homeostatic plasticity. Included in our review are well-established AMPA receptor interactants such as GRIP1 and PICK1, the classical auxiliary subunits TARP and CNIH, and the newest additions to AMPA receptor native complexes.
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Affiliation(s)
- Diane Bissen
- Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany
- Max Planck Institute for Brain Research, Max von Laue Str. 4, 60438, Frankfurt am Main, Germany
| | - Franziska Foss
- Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany
| | - Amparo Acker-Palmer
- Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany.
- Max Planck Institute for Brain Research, Max von Laue Str. 4, 60438, Frankfurt am Main, Germany.
- Cardio-Pulmonary Institute (CPI), Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany.
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27
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Zhang F, Wang Y, Wang T, Yao L, Lam SM, Huang X, Fan J, Wang Q, Liu L, Jiang Y, Zhang H, Shi L, Yu M, Shui G, Wang Y, Gao F, Zhang X, Xu Z. cTAGE5/MEA6 plays a critical role in neuronal cellular components trafficking and brain development. Proc Natl Acad Sci U S A 2018; 115:E9449-E9458. [PMID: 30224460 PMCID: PMC6176567 DOI: 10.1073/pnas.1804083115] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Normal neural development is essential for the formation of neuronal networks and brain function. Cutaneous T cell lymphoma-associated antigen 5 (cTAGE5)/meningioma expressed antigen 6 (MEA6) plays a critical role in the secretion of proteins. However, its roles in the transport of nonsecretory cellular components and in brain development remain unknown. Here, we show that cTAGE5/MEA6 is important for brain development and function. Conditional knockout of cTAGE5/MEA6 in the brain leads to severe defects in neural development, including deficits in dendrite outgrowth and branching, spine formation and maintenance, astrocyte activation, and abnormal behaviors. We reveal that loss of cTAGE5/MEA6 affects the interaction between the coat protein complex II (COPII) components, SAR1 and SEC23, leading to persistent activation of SAR1 and defects in COPII vesicle formation and transport from the endoplasmic reticulum to the Golgi, as well as disturbed trafficking of membrane components in neurons. These defects affect not only the transport of materials required for the development of dendrites and spines but also the signaling pathways required for neuronal development. Because mutations in cTAGE5/MEA6 have been found in patients with Fahr's disease, our study potentially also provides insight into the pathogenesis of this disorder.
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Affiliation(s)
- Feng Zhang
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
- University of Chinese Academy of Sciences, 100101 Beijing, China
| | - Yaqing Wang
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
- University of Chinese Academy of Sciences, 100101 Beijing, China
| | - Tao Wang
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
- University of Chinese Academy of Sciences, 100101 Beijing, China
| | - Li Yao
- State Key Laboratory of Cognitive Neuroscience & Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, 100875 Beijing, China
| | - Sin Man Lam
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Xiahe Huang
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Junwan Fan
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
- University of Chinese Academy of Sciences, 100101 Beijing, China
| | - Qin Wang
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
- University of Chinese Academy of Sciences, 100101 Beijing, China
| | - Liang Liu
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
- University of Chinese Academy of Sciences, 100101 Beijing, China
| | - Yisheng Jiang
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
- University of Chinese Academy of Sciences, 100101 Beijing, China
| | - Hongsheng Zhang
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Lei Shi
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Mei Yu
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Yingchun Wang
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Fei Gao
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Xiaohui Zhang
- State Key Laboratory of Cognitive Neuroscience & Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, 100875 Beijing, China
| | - Zhiheng Xu
- State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China;
- University of Chinese Academy of Sciences, 100101 Beijing, China
- Parkinson's Disease Center, Beijing Institute for Brain Disorders, 100101 Beijing, China
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28
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Yao JJ, Zhao QR, Lu JM, Mei YA. Functions and the related signaling pathways of the neurotrophic factor neuritin. Acta Pharmacol Sin 2018; 39:1414-1420. [PMID: 29595190 PMCID: PMC6289377 DOI: 10.1038/aps.2017.197] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 12/08/2017] [Indexed: 12/29/2022]
Abstract
Neuritin is a member of the neurotrophic factor family, which is activated by neural activity and neurotrophins, and promotes neurite growth and branching. It has shown to play an important role in neuronal plasticity and regeneration. It is also involved in other biological processes such as angiogenesis, tumorigenesis and immunomodulation. Thus far, however, the primary mechanisms of neuritin, including whether or not it acts through a receptor or which downstream signals might be activated following binding, are not fully understood. Recent evidence suggests that neuritin may be a potential therapeutic target in several neurodegenerative diseases. This review focuses on the recent advances in studies regarding the newly identified functions of neuritin and the signaling pathways related to these functions. We also discuss current hot topics and difficulties in neuritin research.
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Affiliation(s)
- Jin-Jing Yao
- Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai, 200433, China
| | - Qian-Ru Zhao
- Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai, 200433, China
| | - Jun-Mei Lu
- Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai, 200433, China
| | - Yan-Ai Mei
- Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai, 200433, China.
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29
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Zhao QR, Lu JM, Li ZY, Mei YA. Neuritin promotes neurite and spine growth in rat cerebellar granule cells via L-type calcium channel-mediated calcium influx. J Neurochem 2018; 147:40-57. [PMID: 29920676 PMCID: PMC6220818 DOI: 10.1111/jnc.14535] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 05/21/2018] [Accepted: 06/13/2018] [Indexed: 01/15/2023]
Abstract
Neuritin is a neurotrophic factor that is activated by neural activity and neurotrophins. Its major function is to promote neurite growth and branching; however, the underlying mechanisms are not fully understood. To address this issue, this study investigated the effects of neuritin on neurite and spine growth and intracellular Ca2+ concentration in rat cerebellar granule neurons (CGNs). Incubation of CGNs for 24 h with neuritin increased neurite length and spine density; this effect was mimicked by insulin and abolished by inhibiting insulin receptor (IR) or mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase (ERK) activity. Calcium imaging and western blot analysis revealed that neuritin enhanced the increase in intracellular Ca2+ level induced by high K+, and stimulated the cell surface expression of CaV1.2 and CaV1.3 α subunits of the L‐type calcium channel, which was suppressed by inhibition of IR or mitogen‐activated protein kinase kinase/ERK. Treatment with inhibitors of L‐type calcium channels, calmodulin, and calcineurin (CaN) abrogated the effects of neuritin on neurite length and spine density. A similar result was obtained by silencing nuclear factor of activated T cells c4, which is known to be activated by neuritin in CGNs. These results indicate that IR and ERK signaling as well as the Ca2+/CaN/nuclear factor of activated T cells c4 axis mediate the effects of neuritin on neurite and spine growth in CGNs. Open Practices
Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ ![]()
Cover Image for this issue: doi: 10.1111/jnc.14195.
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Affiliation(s)
- Qian-Ru Zhao
- Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai, China
| | - Jun-Mei Lu
- Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai, China
| | - Zhao-Yang Li
- Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai, China
| | - Yan-Ai Mei
- Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai, China
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30
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Abstract
Circuit operations are determined jointly by the properties of the circuit elements and the properties of the connections among these elements. In the nervous system, neurons exhibit diverse morphologies and branching patterns, allowing rich compartmentalization within individual cells and complex synaptic interactions among groups of cells. In this review, we summarize work detailing how neuronal morphology impacts neural circuit function. In particular, we consider example neurons in the retina, cerebral cortex, and the stomatogastric ganglion of crustaceans. We also explore molecular coregulators of morphology and circuit function to begin bridging the gap between molecular and systems approaches. By identifying motifs in different systems, we move closer to understanding the structure-function relationships that are present in neural circuits.
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Affiliation(s)
| | - Stephen D Van Hooser
- Department of Biology, Brandeis University , Waltham, Massachusetts.,Volen Center for Complex Systems, Brandeis University , Waltham, Massachusetts.,Sloan-Swartz Center for Theoretical Neurobiology, Brandeis University , Waltham, Massachusetts
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31
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Inoue N, Nishizumi H, Naritsuka H, Kiyonari H, Sakano H. Sema7A/PlxnCl signaling triggers activity-dependent olfactory synapse formation. Nat Commun 2018; 9:1842. [PMID: 29743476 PMCID: PMC5943276 DOI: 10.1038/s41467-018-04239-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 04/13/2018] [Indexed: 11/17/2022] Open
Abstract
In mammals, neural circuits are formed based on a genetic program and further refined by neuronal activity during the neonatal period. We report that in the mouse olfactory system, the glomerular map is not merely refined but newly connected to second-order neurons by odorant-receptor-derived neuronal activity. Here, we analyzed a pair of molecules, Sema7A, expressed in olfactory sensory neurons (OSNs) in an activity-dependent manner, and PlxnC1, localized to dendrites of mitral/tufted (M/T) cells in the first week after birth. In Sema7A or PlxnC1 knockout (KO) mice, initiation of synapse formation and dendrite selection of M/T cells were perturbed. Reconstitution and rescue experiments demonstrated that Sema7A-PlxnC1 interaction is essential to form the post-synaptic assembly. Pharmacological blocking experiments indicated that synaptic transmission triggers primary dendrite selection by synaptic competition. We conclude that Sema7A signaling is key to inducing activity-dependent post-synapse events and dendrite selection in M/T-cells during the neonatal period.
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Affiliation(s)
- Nobuko Inoue
- Department of Brain Function, University of Fukui School of Medicine, 23-3 Shimo-aizuki, Matsuoka, Fukui, 910-1193, Japan
| | - Hirofumi Nishizumi
- Department of Brain Function, University of Fukui School of Medicine, 23-3 Shimo-aizuki, Matsuoka, Fukui, 910-1193, Japan
| | - Hiromi Naritsuka
- Department of Physiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hiroshi Kiyonari
- RIKEN Institute, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Hitoshi Sakano
- Department of Brain Function, University of Fukui School of Medicine, 23-3 Shimo-aizuki, Matsuoka, Fukui, 910-1193, Japan.
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32
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Synapse development organized by neuronal activity-regulated immediate-early genes. Exp Mol Med 2018; 50:1-7. [PMID: 29628504 PMCID: PMC5938016 DOI: 10.1038/s12276-018-0025-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 11/29/2017] [Indexed: 02/07/2023] Open
Abstract
Classical studies have shown that neuronal immediate-early genes (IEGs) play important roles in synaptic processes critical for key brain functions. IEGs are transiently activated and rapidly upregulated in discrete neurons in response to a wide variety of cellular stimuli, and they are uniquely involved in various aspects of synapse development. In this review, we summarize recent studies of a subset of neuronal IEGs in regulating synapse formation, transmission, and plasticity. We also discuss how the dysregulation of neuronal IEGs is associated with the onset of various brain disorders and pinpoint key outstanding questions that should be addressed in this field. Immediate-early genes (IEGs), genes that are rapidly and transiently activated by cellular stimuli, regulate the interactions between neurons and key brain functions. Ji Won Um and colleagues at Daegu Gyeongbuk Institute of Science and Technology in South Korea review recent studies on three IEGs that are activated by neuronal activity and highlight their contribution to neuronal excitability and cognitive behaviors. These genes rely on different molecular mechanisms to regulate neuronal receptors and the structure of synapses. Research in mice lacking any one of these IEGs reveals their contribution to learning and memory as well as to some behavioral abnormalities associated with neuropsychiatric disorders. Further research into the activity of IEGs will advance our understanding of how a neuron’s environment influences brain development and disease.
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Dong H, Luo X, Niu Y, Yu N, Gao R, Wang H, Yang L, Huang J. Neuritin 1 expression in human normal tissues and its association with various human cancers. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:1956-1964. [PMID: 31938301 PMCID: PMC6958223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 03/28/2018] [Indexed: 06/10/2023]
Abstract
OBJECTIVE(S) Neuritin (Nrn1) is a glycophosphatidylinositol-linked protein that can be induced by neural activity in the central nervous system. However, its expression outside the nervous system and association with human cancers is unclear. This study investigated the expression of Nrn1 in human tissues as well as its association with human cancers. MATERIALS AND METHODS Nrn1 gene expression in human adult tissues was evaluated with the Clontech Multiple Tissue cDNA panel. Nrn1 protein in various tissues was detected by immunohistochemistry. Signal v.4.0 and TMHMM v.2.0 software were used to identify the signal peptide and transmembrane helix of Nrn1. The subcellular localization of Nrn1 in cultured SH-SY5Y cells was assessed by immunocytochemistry and western blotting. The expression of Nrn1 in human cancers were assessed using the online tools GEPIA. RESULTS Nrn1 mRNA was expressed in various tissues, compared to mRNA levels in the brain tissues, expression was high in the placenta, lungs, skeletal muscle, thymus, pancreas, liver and the heart tissues; lower levels were detected in the small intestine, ovary, spleen, and testes, but there was no detectable expression in the kidneys, colon, prostate or leukocytes. In SY5Y cells, Nrn1 was colocalized with caveolin 1 at the plasma membrane. Nrn1 was downregulated in Bladder Urothelial Carcinoma (BLCA); Breast invasive carcinoma (BRCA); Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC); Colon adenocarcinoma (COAD); Glioblastoma multiforme (GBM); Kidney Chromophobe (KIHC); Kidney renal papillary cell carcinoma (KIRP); Lower Grade GLioma (LGG); Rectum adenocarcinoma (READ); Uterine Corpus Endometrial Carcinoma (UCEC); Lung adenocarcinoma (LUA), Ovarian serous cystadenocarcinoma (OV) and upregulated in Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC). A combination of the overall survival analysis of the 12 kinds of human tumors with Nrn1 downregulation revealed that patients with high levels of Nrn1 present a long term survival. But there is no significant effect on DLBC patients' survival. CONCLUSION Nrn1 is expressed in various human tissues including the nervous system, specifically in the lipid rafts of cell membranes. We also provided the strong evidence that Nrn1 is associated with 13 kinds of human cancers and could function as biomarkers and therapeutic targets for these cancers.
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Affiliation(s)
- Hongchang Dong
- Department of Biochemistry, The Key Laboratory of Xinjiang Endemic & Ethnic Diseases, School of Medicine, Shihezi UniversityShihezi 832002, Xinjiang, China
| | - Xing Luo
- Department of Biochemistry, The Key Laboratory of Xinjiang Endemic & Ethnic Diseases, School of Medicine, Shihezi UniversityShihezi 832002, Xinjiang, China
| | - Yuqin Niu
- Medical Center of The Affiliated Hospital of Shihezi UniversityShihezi, Xinjiang, China
| | - Na Yu
- Department of Biochemistry, The Key Laboratory of Xinjiang Endemic & Ethnic Diseases, School of Medicine, Shihezi UniversityShihezi 832002, Xinjiang, China
| | - Rui Gao
- Department of Biochemistry, The Key Laboratory of Xinjiang Endemic & Ethnic Diseases, School of Medicine, Shihezi UniversityShihezi 832002, Xinjiang, China
| | - Haiyan Wang
- Department of Biochemistry, The Key Laboratory of Xinjiang Endemic & Ethnic Diseases, School of Medicine, Shihezi UniversityShihezi 832002, Xinjiang, China
- Hangzhou Normal UniversityHangzhou, Zhejiang, China
| | - Li Yang
- Department of Biochemistry, The Key Laboratory of Xinjiang Endemic & Ethnic Diseases, School of Medicine, Shihezi UniversityShihezi 832002, Xinjiang, China
| | - Jin Huang
- Department of Biochemistry, The Key Laboratory of Xinjiang Endemic & Ethnic Diseases, School of Medicine, Shihezi UniversityShihezi 832002, Xinjiang, China
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Bosserhoff AK, Schneider N, Ellmann L, Heinzerling L, Kuphal S. The neurotrophin Neuritin1 (cpg15) is involved in melanoma migration, attachment independent growth, and vascular mimicry. Oncotarget 2018; 8:1117-1131. [PMID: 27901477 PMCID: PMC5352040 DOI: 10.18632/oncotarget.13585] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 11/07/2016] [Indexed: 01/20/2023] Open
Abstract
The neurotrophin Neuritin1 (NRN1; cpg15) belongs to the candidate plasticity gene (CPG) family and is expressed in postmitotic-differentiating neurons of the developmental nervous system and neuronal structures associated with plasticity in the brain of human adult.Our newest findings document that NRN1 deregulation could contribute also to disease development and have impact on malignant melanoma. Our analyses displayed the over-expression of NRN1 in melanoma in vitro and in vivo, shown by immunohistochemistry and qRT-PCR on microdissected melanoma tissue; furthermore, soluble NRN1 was detectable in tissue culture supernatant and serum of melanoma patients.To investigate the role of NRN1 in melanoma we performed knockdown, over-expression and recombinant-NRN1-treatment experiments affiliated by functional assays. Our results show that migration, attachment independent growth and vasculogenesis were affected after manipulation of NRN1 on endogenous and extrinsic level. Interestingly, high NRN1 serum levels correlate with low MIA serum levels (< 10ng/ml). Therefore, we speculate that NRN1 could be a marker for early melanoma stages, in particular.In summary, we detected an overexpression of NRN1 in melanoma patient. In functional cell culture experiments we found a correlation between NRN1 expression and the cancerous behavior of melanoma cells.
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Affiliation(s)
- Anja Katrin Bosserhoff
- Institute of Biochemistry (Emil-Fischer-Center), Friedrich Alexander University Erlangen-Nürnberg, Erlangen, 91054, Germany
| | - Nadja Schneider
- Institute of Biochemistry (Emil-Fischer-Center), Friedrich Alexander University Erlangen-Nürnberg, Erlangen, 91054, Germany
| | - Lisa Ellmann
- Institute for Functional Genomics, University Regensburg, Regensburg, 93053, Germany
| | - Lucie Heinzerling
- Institute of Dermatology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, 91054, Germany
| | - Silke Kuphal
- Institute of Biochemistry (Emil-Fischer-Center), Friedrich Alexander University Erlangen-Nürnberg, Erlangen, 91054, Germany
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Monavarfeshani A, Stanton G, Van Name J, Su K, Mills WA, Swilling K, Kerr A, Huebschman NA, Su J, Fox MA. LRRTM1 underlies synaptic convergence in visual thalamus. eLife 2018; 7:e33498. [PMID: 29424692 PMCID: PMC5826289 DOI: 10.7554/elife.33498] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 02/08/2018] [Indexed: 11/13/2022] Open
Abstract
It has long been thought that the mammalian visual system is organized into parallel pathways, with incoming visual signals being parsed in the retina based on feature (e.g. color, contrast and motion) and then transmitted to the brain in unmixed, feature-specific channels. To faithfully convey feature-specific information from retina to cortex, thalamic relay cells must receive inputs from only a small number of functionally similar retinal ganglion cells. However, recent studies challenged this by revealing substantial levels of retinal convergence onto relay cells. Here, we sought to identify mechanisms responsible for the assembly of such convergence. Using an unbiased transcriptomics approach and targeted mutant mice, we discovered a critical role for the synaptic adhesion molecule Leucine Rich Repeat Transmembrane Neuronal 1 (LRRTM1) in the emergence of retinothalamic convergence. Importantly, LRRTM1 mutant mice display impairment in visual behaviors, suggesting a functional role of retinothalamic convergence in vision.
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Affiliation(s)
- Aboozar Monavarfeshani
- Developmental and Translational Neurobiology CenterVirginia Tech Carilion Research InstituteRoanokeUnited States
- Department of Biological SciencesVirginia TechBlacksburgUnited States
| | - Gail Stanton
- Developmental and Translational Neurobiology CenterVirginia Tech Carilion Research InstituteRoanokeUnited States
- Virginia Tech Carilion School of MedicineRoanokeUnited States
| | - Jonathan Van Name
- Developmental and Translational Neurobiology CenterVirginia Tech Carilion Research InstituteRoanokeUnited States
| | - Kaiwen Su
- Developmental and Translational Neurobiology CenterVirginia Tech Carilion Research InstituteRoanokeUnited States
| | - William A Mills
- Developmental and Translational Neurobiology CenterVirginia Tech Carilion Research InstituteRoanokeUnited States
- Translational Biology, Medicine, and Health Graduate ProgramVirginia TechBlacksburgUnited States
| | - Kenya Swilling
- Developmental and Translational Neurobiology CenterVirginia Tech Carilion Research InstituteRoanokeUnited States
| | - Alicia Kerr
- Developmental and Translational Neurobiology CenterVirginia Tech Carilion Research InstituteRoanokeUnited States
- Translational Biology, Medicine, and Health Graduate ProgramVirginia TechBlacksburgUnited States
| | | | - Jianmin Su
- Developmental and Translational Neurobiology CenterVirginia Tech Carilion Research InstituteRoanokeUnited States
| | - Michael A Fox
- Developmental and Translational Neurobiology CenterVirginia Tech Carilion Research InstituteRoanokeUnited States
- Department of Biological SciencesVirginia TechBlacksburgUnited States
- Virginia Tech Carilion School of MedicineRoanokeUnited States
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Liu Q, Zhang H, Xu J, Zhao D. Neuritin provides neuroprotection against experimental traumatic brain injury in rats. Int J Neurosci 2018; 128:811-820. [PMID: 29334295 DOI: 10.1080/00207454.2018.1424155] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVES Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Neuritin is a neurotrophic factor that regulates neural growth and development. However, the role of neuritin in alleviating TBI has not been investigated. METHODS In this study, Sprague Dawley rats (n = 144) weighing 300 ± 50 g were categorized into control, sham, TBI and TBI + neuritin groups. The neurological scores and the ultrastructure of cortical neurons, apoptotic cells and caspase-3 were measured by using Garcia scoring system, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Western blot analysis and real-time RT-PCR at various time points post-TBI. CONCLUSIONS Our findings indicated that neuritin plays a protective role in TBI by improving neurological scores, repairing injured neurons and protecting the cortical neurons against apoptosis through inhibition of caspase-3 expression. Further investigation of the molecular mechanisms underlying caspase-3 inhibition by neuritin will provide a research avenue for potential TBI therapeutics.
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Affiliation(s)
- Qi Liu
- a Department of Neurosurgery , First Affiliated Hospital of Medical College, Shihezi University , Shihezi , Xinjiang , China.,b The Key Laboratory of Xinjiang Endemic and Ethnic Diseases , Medical College of Shihezi University , Shihezi , Xinjiang , China
| | - Hang Zhang
- a Department of Neurosurgery , First Affiliated Hospital of Medical College, Shihezi University , Shihezi , Xinjiang , China.,b The Key Laboratory of Xinjiang Endemic and Ethnic Diseases , Medical College of Shihezi University , Shihezi , Xinjiang , China
| | - Jian Xu
- a Department of Neurosurgery , First Affiliated Hospital of Medical College, Shihezi University , Shihezi , Xinjiang , China.,b The Key Laboratory of Xinjiang Endemic and Ethnic Diseases , Medical College of Shihezi University , Shihezi , Xinjiang , China
| | - Dong Zhao
- a Department of Neurosurgery , First Affiliated Hospital of Medical College, Shihezi University , Shihezi , Xinjiang , China.,b The Key Laboratory of Xinjiang Endemic and Ethnic Diseases , Medical College of Shihezi University , Shihezi , Xinjiang , China
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Abstract
During development, the environment exerts a profound influence on the wiring of brain circuits. Due to the limited resolution of studies in fixed tissue, this experience-dependent structural plasticity was once thought to be restricted to a specific developmental time window. The recent introduction of two-photon microscopy for in vivo imaging has opened the door to repeated monitoring of individual neurons and the study of structural plasticity mechanisms at a very fine scale. In this review, we focus on recent work showing that synaptic structural rearrangements are a key mechanism mediating neural circuit adaptation and behavioral plasticity in the adult brain. We examine this work in the context of classic studies in the visual systems of model organisms, which have laid much of the groundwork for our understanding of activity-dependent synaptic remodeling and its role in brain plasticity.
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Affiliation(s)
- Kalen P Berry
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; .,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
| | - Elly Nedivi
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; .,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.,Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
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Thyroid Hormone Acts Locally to Increase Neurogenesis, Neuronal Differentiation, and Dendritic Arbor Elaboration in the Tadpole Visual System. J Neurosci 2017; 36:10356-10375. [PMID: 27707971 DOI: 10.1523/jneurosci.4147-15.2016] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 08/01/2016] [Indexed: 11/21/2022] Open
Abstract
Thyroid hormone (TH) regulates many cellular events underlying perinatal brain development in vertebrates. Whether and how TH regulates brain development when neural circuits are first forming is less clear. Furthermore, although the molecular mechanisms that impose spatiotemporal constraints on TH action in the brain have been described, the effects of local TH signaling are poorly understood. We determined the effects of manipulating TH signaling on development of the optic tectum in stage 46-49 Xenopus laevis tadpoles. Global TH treatment caused large-scale morphological effects in tadpoles, including changes in brain morphology and increased tectal cell proliferation. Either increasing or decreasing endogenous TH signaling in tectum, by combining targeted DIO3 knockdown and methimazole, led to corresponding changes in tectal cell proliferation. Local increases in TH, accomplished by injecting suspensions of tri-iodothyronine (T3) in coconut oil into the midbrain ventricle or into the eye, selectively increased tectal or retinal cell proliferation, respectively. In vivo time-lapse imaging demonstrated that local TH first increased tectal progenitor cell proliferation, expanding the progenitor pool, and subsequently increased neuronal differentiation. Local T3 also dramatically increased dendritic arbor growth in neurons that had already reached a growth plateau. The time-lapse data indicate that the same cells are differentially sensitive to T3 at different time points. Finally, TH increased expression of genes pertaining to proliferation and neuronal differentiation. These experiments indicate that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting cell proliferation and differentiation and by acting on neurons to increase dendritic arbor elaboration. SIGNIFICANCE STATEMENT Thyroid hormone (TH) is a critical regulator of perinatal brain development in vertebrates. Abnormal TH signaling in early pregnancy is associated with significant cognitive deficits in humans; however, it is difficult to probe the function of TH in early brain development in mammals because of the inaccessibility of the fetal brain in the uterine environment and the challenge of disambiguating maternal versus fetal contributions of TH. The external development of tadpoles allows manipulation and direct observation of the molecular and cellular mechanisms underlying TH's effects on brain development in ways not possible in mammals. We find that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting neural progenitor cell proliferation and differentiation and by acting on neurons to enhance dendritic arbor elaboration.
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Zhang H, He X, Wang Y, Sun X, Zhu L, Lei C, Yin J, Li X, Hou F, He W, Zhao D. Neuritin attenuates early brain injury in rats after experimental subarachnoid hemorrhage. Int J Neurosci 2017; 127:1087-1095. [PMID: 28562156 DOI: 10.1080/00207454.2017.1337013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Hang Zhang
- Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Xuejun He
- Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Yezhong Wang
- Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Xiaokun Sun
- Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Licang Zhu
- Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Chao Lei
- Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Jiangwen Yin
- Department of Anesthesiology, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Xiaotian Li
- Department of Neurosurgery, Weifang People's HospitalWeifang, Shandong, China
| | - Fandi Hou
- Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Wengao He
- Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
| | - Dong Zhao
- Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Xinjiang, China
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Zhang P, Luo X, Guo Z, Xiong A, Dong H, Zhang Q, Liu C, Zhu J, Wang H, Yu N, Zhang J, Hong Y, Yang L, Huang J. Neuritin Inhibits Notch Signaling through Interacted with Neuralized to Promote the Neurite Growth. Front Mol Neurosci 2017. [PMID: 28642682 PMCID: PMC5462965 DOI: 10.3389/fnmol.2017.00179] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Neuritin plays a key role in neural development and regeneration by promoting neurite outgrowth and synapse maturation. However, the mechanism of neuritin in modulating neurite growth has not been elucidated. Here, using yeast two-hybrid we screened and discovered the interaction of neuritin and neuralized (NEURL1), which is an important regulator that can activate Notch signaling through promoting endocytosis of Notch ligand. And then we identified the interaction of neuritin and neuralized by co-immunoprecipitation (IP) assays, and clarified that neuritin and NEURL1 were co-localized on the cell membrane of SH-SY5Y cells. Moreover, neuritin significantly suppressed Notch ligand Jagged1 (JAG1) endocytosis promoted by NEURL1, and then inhibited the activation of Notch receptor Notch intracellular domain (NICD) and decreased the expression of downstream gene hairy and enhancer of split-1 (HES1). Importantly, the effect of neuritin on inhibiting Notch signaling was rescued by NEURL1, which indicated that neuritin is an upstream and negative regulator of NEURL1 to inhibit Notch signaling through interaction with NEURL1. Notably, recombinant neuritin restored the retraction of neurites caused by activation of Notch, and neurite growth stimulated by neuritin was partially blocked by NEURL1. These findings establish neuritin as an upstream and negative regulator of NEURL1 that inhibits Notch signaling to promote neurite growth. This mechanism connects neuritin with Notch signaling, and provides a valuable foundation for further investigation of neuritin's role in neurodevelopment and neural plasticity.
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Affiliation(s)
- Pan Zhang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Xing Luo
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Zheng Guo
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Anying Xiong
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Hongchang Dong
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Qiao Zhang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Chunyan Liu
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Jingling Zhu
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Haiyan Wang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Na Yu
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Jinli Zhang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
| | - Yu Hong
- School of Medicine, Hangzhou Normal UniversityHangzhou, China
| | - Lei Yang
- School of Medicine, Hangzhou Normal UniversityHangzhou, China
| | - Jin Huang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, Shihezi University School of MedicineShihezi, China
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Lu JM, Liu DD, Li ZY, Ling C, Mei YA. Neuritin Enhances Synaptic Transmission in Medial Prefrontal Cortex in Mice by Increasing CaV3.3 Surface Expression. Cereb Cortex 2017; 27:3842-3855. [DOI: 10.1093/cercor/bhx082] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 03/23/2017] [Indexed: 02/02/2023] Open
Affiliation(s)
- Jun-Mei Lu
- State Key Laboratory of Medical Neurobiology and School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai 200433, China
| | - Dong-Dong Liu
- State Key Laboratory of Medical Neurobiology and School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai 200433, China
| | - Zhao-Yang Li
- State Key Laboratory of Medical Neurobiology and School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai 200433, China
| | - Chen Ling
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yan-Ai Mei
- State Key Laboratory of Medical Neurobiology and School of Life Sciences, Institutes of Brain Science, Fudan University, Shanghai 200433, China
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Soluble cpg15 from Astrocytes Ameliorates Neurite Outgrowth Recovery of Hippocampal Neurons after Mouse Cerebral Ischemia. J Neurosci 2017; 37:1628-1647. [PMID: 28069924 DOI: 10.1523/jneurosci.1611-16.2016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 12/22/2016] [Accepted: 12/30/2016] [Indexed: 11/21/2022] Open
Abstract
The present study focuses on the function of cpg15, a neurotrophic factor, in ischemic neuronal recovery using transient global cerebral ischemic (TGI) mouse model and oxygen-glucose deprivation (OGD)-treated primary cultured cells. The results showed that expression of cpg15 proteins in astrocytes, predominantly the soluble form, was significantly increased in mouse hippocampus after TGI and in the cultured astrocytes after OGD. Addition of the medium from the cpg15-overexpressed astrocytic culture into the OGD-treated hippocampal neuronal cultures reduces the neuronal injury, whereas the recovery of neurite outgrowths of OGD-injured neurons was prevented when cpg15 in the OGD-treated astrocytes was knocked down, or the OGD-treated-astrocytic medium was immunoadsorbed by cpg15 antibody. Furthermore, lentivirus-delivered knockdown of cpg15 expression in mouse hippocampal astrocytes diminishes the dendritic branches and exacerbates injury of neurons in CA1 region after TGI. In addition, treatment with inhibitors of MEK1/2, PI3K, and TrkA decreases, whereas overexpression of p-CREB, but not dp-CREB, increases the expression of cpg15 in U118 or primary cultured astrocytes. Also, it is observed that the Flag-tagged soluble cpg15 from the astrocytes transfected with Flag-tagged cpg15-expressing plasmids adheres to the surface of neuronal bodies and the neurites. In conclusion, our results suggest that the soluble cpg15 from astrocytes induced by ischemia could ameliorate the recovery of the ischemic-injured hippocampal neurons via adhering to the surface of neurons. The upregulated expression of cpg15 in astrocytes may be activated via MAPK and PI3K signal pathways, and regulation of CREB phosphorylation.SIGNIFICANCE STATEMENT Neuronal plasticity plays a crucial role in the amelioration of neurological recovery of ischemic injured brain, which remains a challenge for clinic treatment of cerebral ischemia. cpg15 as a synaptic plasticity-related factor may participate in promoting the recovery process; however, the underlying mechanisms are still largely unknown. The objective of this study is to reveal the function and mechanism of neuronal-specific cpg15 expressed in astrocytes after ischemia induction, in promoting the recovery of injured neurons. Our findings provided new mechanistic insight into the neurological recovery, which might help develop novel therapeutic options for cerebral ischemia via astrocytic-targeting interference of gene expression.
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Wang H, Li X, Shan L, Zhu J, Chen R, Li Y, Yuan W, Yang L, Huang J. Recombinant hNeuritin Promotes Structural and Functional Recovery of Sciatic Nerve Injury in Rats. Front Neurosci 2016; 10:589. [PMID: 28066172 PMCID: PMC5177646 DOI: 10.3389/fnins.2016.00589] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 12/08/2016] [Indexed: 01/29/2023] Open
Abstract
Neuritin is a new neurotropic factor implicated in nervous system development and plasticity. Studies have shown that Neuritin is upregulated in injured nerves, suggesting that it is involved in nerve repair. To test this hypothesis, we investigated whether recombinant human Neuritin could restore nerve structure and function in a rat model of sciatic nerve injury. Neuritin treatment had a dose-dependent effect on functional recovery 4 weeks after injury, as determined by the walking-track test. Similar trends were observed for gastrocnemius muscular strength and nerve conduction velocity. Additionally, sciatic nerve fiber density and organization as well as degree of remyelination were increased, while growth-associated protein 43 and neurofilament 200 expression was upregulated upon treatment with Neuritin. These findings demonstrate that Neuritin stimulates nerve regeneration and functional recovery and thus promotes the repair of injured sciatic nerves.
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Affiliation(s)
- Haiyan Wang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine Shihezi, China
| | - Xinli Li
- Laboratory Medicine Department of Sixth People's Hospital of Chengdu, Chengdu, China
| | - Liya Shan
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine Shihezi, China
| | - Jingling Zhu
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine Shihezi, China
| | - Rong Chen
- Occupational and Environmental Health, Department of Preventive Medicine, School of Medicine, Hangzhou Normal University Hangzhou, China
| | - Yuan Li
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Hangzhou Normal University Hangzhou, China
| | - Wumei Yuan
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine Shihezi, China
| | - Lei Yang
- Occupational and Environmental Health, Department of Preventive Medicine, School of Medicine, Hangzhou Normal University Hangzhou, China
| | - Jin Huang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine Shihezi, China
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Leijon SC, Peyda S, Magnusson AK. Temporal processing capacity in auditory-deprived superior paraolivary neurons is rescued by sequential plasticity during early development. Neuroscience 2016; 337:315-330. [DOI: 10.1016/j.neuroscience.2016.09.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 09/01/2016] [Accepted: 09/09/2016] [Indexed: 01/04/2023]
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Pratt KG, Hiramoto M, Cline HT. An Evolutionarily Conserved Mechanism for Activity-Dependent Visual Circuit Development. Front Neural Circuits 2016; 10:79. [PMID: 27818623 PMCID: PMC5073143 DOI: 10.3389/fncir.2016.00079] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/26/2016] [Indexed: 12/01/2022] Open
Abstract
Neural circuit development is an activity-dependent process. This activity can be spontaneous, such as the retinal waves that course across the mammalian embryonic retina, or it can be sensory-driven, such as the activation of retinal ganglion cells (RGCs) by visual stimuli. Whichever the source, neural activity provides essential instruction to the developing circuit. Indeed, experimentally altering activity has been shown to impact circuit development and function in many different ways and in many different model systems. In this review, we contemplate the idea that retinal waves in amniotes, the animals that develop either in ovo or utero (namely reptiles, birds and mammals) could be an evolutionary adaptation to life on land, and that the anamniotes, animals whose development is entirely external (namely the aquatic amphibians and fish), do not display retinal waves, most likely because they simply don’t need them. We then review what is known about the function of both retinal waves and visual stimuli on their respective downstream targets, and predict that the experience-dependent development of the tadpole visual system is a blueprint of what will be found in future studies of the effects of spontaneous retinal waves on instructing development of retinorecipient targets such as the superior colliculus (SC) and the lateral geniculate nucleus.
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Affiliation(s)
- Kara G Pratt
- Program in Neuroscience, Department of Zoology and Physiology, University of Wyoming Laramie, WY, USA
| | - Masaki Hiramoto
- Department of Molecular and Cellular Neuroscience and The Dorris Neuroscience Center, The Scripps Research Institute La Jolla, CA, USA
| | - Hollis T Cline
- Department of Molecular and Cellular Neuroscience and The Dorris Neuroscience Center, The Scripps Research Institute La Jolla, CA, USA
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Neuritin Mediates Activity-Dependent Axonal Branch Formation in Part via FGF Signaling. J Neurosci 2016; 36:4534-48. [PMID: 27098696 DOI: 10.1523/jneurosci.1715-15.2016] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 03/09/2016] [Indexed: 11/21/2022] Open
Abstract
UNLABELLED Aberrant branch formation of granule cell axons (mossy fiber sprouting) is observed in the dentate gyrus of many patients with temporal lobe epilepsy and in animal models of epilepsy. However, the mechanisms underlying mossy fiber sprouting remain elusive. Based on the hypothesis that seizure-mediated gene expression induces abnormal mossy fiber growth, we screened activity-regulated genes in the hippocampus and found that neuritin, an extracellular protein anchored to the cell surface, was rapidly upregulated after electroconvulsive seizures. Overexpression of neuritin in the cultured rat granule cells promoted their axonal branching. Also, kainic acid-dependent axonal branching was abolished in the cultured granule cells fromneuritinknock-out mice, suggesting that neuritin may be involved in activity-dependent axonal branching. Moreover,neuritinknock-out mice showed less-severe seizures in chemical kindling probably by reduced mossy fiber sprouting and/or increased seizure resistance. We found that inhibition of the fibroblast growth factor (FGF) receptor attenuated the neuritin-dependent axonal branching. FGF administration also increased branching in granule neurons, whereasneuritinknock-out mice did not show FGF-dependent axonal branching. In addition, FGF and neuritin treatment enhanced the recruitment of FGF receptors to the cell surface. These findings suggest that neuritin and FGF cooperate in inducing mossy fiber sprouting through FGF signaling. Together, these results suggest that FGF and neuritin-mediated axonal branch induction are involved in the aggravation of epilepsy. SIGNIFICANCE STATEMENT This study reveals the molecular mechanism underlying mossy fiber sprouting. Mossy fiber sprouting is the aberrant axonal branching of granule neurons in the hippocampus, which is observed in patients with epilepsy. Excess amounts of neuritin, a protein upregulated by neural activity, promoted axonal branching in granule neurons. A deficiency of neuritin suppressed mossy fiber sprouting and resulted in mitigation of seizure severity. Neuritin and fibroblast growth factor (FGF) cooperated in stimulating FGF signaling and enhancing axonal branching. Neuritin is necessary for FGF-mediated recruitment of FGF receptors to the cell surface. The recruitment of FGF receptors would promote axonal branching. The discovery of this new mechanism should contribute to the development of novel antiepileptic drugs to inhibit axonal branching via neuritin-FGF signaling.
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Gao R, Li X, Xi S, Wang H, Zhang H, Zhu J, Shan L, Song X, Luo X, Yang L, Huang J. Exogenous Neuritin Promotes Nerve Regeneration After Acute Spinal Cord Injury in Rats. Hum Gene Ther 2016; 27:544-54. [DOI: 10.1089/hum.2015.159] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Rui Gao
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Xingyi Li
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Shaosong Xi
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Haiyan Wang
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Hong Zhang
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Jingling Zhu
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Liya Shan
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Xiaoming Song
- School of Medicine & Health Management, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xing Luo
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Lei Yang
- School of Medicine & Health Management, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jin Huang
- The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang, China
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Song MY, Tian FF, Dang J, Huang WJ, Guo JL. Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting Under Conditions of Pentylenetetrazole Kindling. NEUROPHYSIOLOGY+ 2015. [DOI: 10.1007/s11062-015-9533-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Zhao QR, Lu JM, Yao JJ, Zhang ZY, Ling C, Mei YA. Neuritin reverses deficits in murine novel object associative recognition memory caused by exposure to extremely low-frequency (50 Hz) electromagnetic fields. Sci Rep 2015; 5:11768. [PMID: 26138388 PMCID: PMC4650637 DOI: 10.1038/srep11768] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 06/01/2015] [Indexed: 12/21/2022] Open
Abstract
Animal studies have shown that electromagnetic field exposure may interfere with the activity of brain cells, thereby generating behavioral and cognitive disturbances. However, the underlying mechanisms and possible preventions are still unknown. In this study, we used a mouse model to examine the effects of exposure to extremely low-frequency (50 Hz) electromagnetic fields (ELF MFs) on a recognition memory task and morphological changes of hippocampal neurons. The data showed that ELF MFs exposure (1 mT, 12 h/day) induced a time-dependent deficit in novel object associative recognition memory and also decreased hippocampal dendritic spine density. This effect was observed without corresponding changes in spontaneous locomotor activity and was transient, which has only been seen after exposing mice to ELF MFs for 7-10 days. The over-expression of hippocampal neuritin, an activity-dependent neurotrophic factor, using an adeno-associated virus (AAV) vector significantly increased the neuritin level and dendritic spine density. This increase was paralleled with ELF MFs exposure-induced deficits in recognition memory and reductions of dendritic spine density. Collectively, our study provides evidence for the association between ELF MFs exposure, impairment of recognition memory, and resulting changes in hippocampal dendritic spine density. Neuritin prevented this ELF MFs-exposure-induced effect by increasing the hippocampal spine density.
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Affiliation(s)
- Qian-Ru Zhao
- Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200433, China
| | - Jun-Mei Lu
- Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200433, China
| | - Jin-Jing Yao
- Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200433, China
| | - Zheng-Yu Zhang
- Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200433, China
| | - Chen Ling
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32611, USA
| | - Yan-Ai Mei
- Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200433, China
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Sharma TP, Liu Y, Wordinger RJ, Pang IH, Clark AF. Neuritin 1 promotes retinal ganglion cell survival and axonal regeneration following optic nerve crush. Cell Death Dis 2015; 6:e1661. [PMID: 25719245 PMCID: PMC4669798 DOI: 10.1038/cddis.2015.22] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 12/11/2014] [Accepted: 01/06/2015] [Indexed: 12/16/2022]
Abstract
Neuritin 1 (Nrn1) is an extracellular glycophosphatidylinositol-linked protein that stimulates axonal plasticity, dendritic arborization and synapse maturation in the central nervous system (CNS). The purpose of this study was to evaluate the neuroprotective and axogenic properties of Nrn1 on axotomized retinal ganglion cells (RGCs) in vitro and on the in vivo optic nerve crush (ONC) mouse model. Axotomized cultured RGCs treated with recombinant hNRN1 significantly increased survival of RGCs by 21% (n=6–7, P<0.01) and neurite outgrowth in RGCs by 141% compared to controls (n=15, P<0.05). RGC transduction with AAV2-CAG–hNRN1 prior to ONC promoted RGC survival (450%, n=3–7, P<0.05) and significantly preserved RGC function by 70% until 28 days post crush (dpc) (n=6, P<0.05) compared with the control AAV2-CAG–green fluorescent protein transduction group. Significantly elevated levels of RGC marker, RNA binding protein with multiple splicing (Rbpms; 73%, n=5–8, P<0.001) and growth cone marker, growth-associated protein 43 (Gap43; 36%, n=3, P<0.01) were observed 28 dpc in the retinas of the treatment group compared with the control group. Significant increase in Gap43 (100%, n=5–6, P<0.05) expression was observed within the optic nerves of the AAV2–hNRN1 group compared to controls. In conclusion, Nrn1 exhibited neuroprotective, regenerative effects and preserved RGC function on axotomized RGCs in vitro and after axonal injury in vivo. Nrn1 is a potential therapeutic target for CNS neurodegenerative diseases.
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Affiliation(s)
- T P Sharma
- 1] North Texas Eye Research Institute, University of North Texas Health Science Center, Ft. Worth, TX 76107, USA [2] Department of Cell Biology & Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Y Liu
- 1] North Texas Eye Research Institute, University of North Texas Health Science Center, Ft. Worth, TX 76107, USA [2] Department of Cell Biology & Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - R J Wordinger
- 1] North Texas Eye Research Institute, University of North Texas Health Science Center, Ft. Worth, TX 76107, USA [2] Department of Cell Biology & Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - I-H Pang
- 1] North Texas Eye Research Institute, University of North Texas Health Science Center, Ft. Worth, TX 76107, USA [2] Department of Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Ft. Worth, TX 76107, USA
| | - A F Clark
- 1] North Texas Eye Research Institute, University of North Texas Health Science Center, Ft. Worth, TX 76107, USA [2] Department of Cell Biology & Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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