|
1
|
Xie L, Qin J, Wang T, Zhang S, Luo M, Cheng X, Cao X, Wang H, Yao B, Xu D, Peng B. Impact of Prenatal Acetaminophen Exposure for Hippocampal Development Disorder on Mice. Mol Neurobiol 2023; 60:6916-6930. [PMID: 37516664 DOI: 10.1007/s12035-023-03515-4] [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: 05/10/2023] [Accepted: 07/14/2023] [Indexed: 07/31/2023]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic agents. They have been detected in various environmental matrices. The degradation of environmental contaminants and the long-term adverse effects have become a major public concern. Prenatal exposure to acetaminophen can cause damage to the developing hippocampus. However, the molecular mechanisms behind hippocampal damage following prenatal acetaminophen exposure (PAcE) remain unclear. The present study shows an increased risk of adverse neurodevelopmental outcomes in offspring following exposure to acetaminophen during pregnancy on mice. The results revealed that different doses, timings, and duration of exposure to acetaminophen during pregnancy were associated with dose-dependent changes in the hippocampus of the offspring. Furthermore, exposure to high doses, multiple-treatment courses, and late pregnancy induced pathological changes, such as wrinkling and vacuolation, inhibited hippocampal proliferation and increased apoptosis. In addition, PAcE significantly decreased the expression of genes related to synaptic development in fetal hippocampal neurons and hippocampal astrocyte and microglia were also damaged to varying degrees. The significant reduction either in SOX2, an essential gene in regulating neural progenitor cell proliferation, and reduction of genes related to the SOX2/Notch pathway may suggest that the role of SOX2/Notch pathway in impaired hippocampal development in the offspring due to PAcE. In general, PAcE at high doses, multiple-treatment courses, and mid- and late gestation were associated with neurodevelopmental toxicity to the offspring.
Collapse
Affiliation(s)
- Lulu Xie
- Department of Pharmacology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
- Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiaxin Qin
- Department of Pharmacology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
- Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tingting Wang
- Department of Pharmacology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Shuai Zhang
- Department of Pharmacology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Mingcui Luo
- Department of Pharmacology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Xuelei Cheng
- Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Xinrui Cao
- Department of Pharmacology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Hui Wang
- Department of Pharmacology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China
| | - Baozhen Yao
- Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan, China.
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China.
| | - Dan Xu
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China.
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
| | - Biwen Peng
- Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China.
| |
Collapse
|
|
2
|
Mukhtar T, Breda J, Adam MA, Boareto M, Grobecker P, Karimaddini Z, Grison A, Eschbach K, Chandrasekhar R, Vermeul S, Okoniewski M, Pachkov M, Harwell CC, Atanasoski S, Beisel C, Iber D, van Nimwegen E, Taylor V. Temporal and sequential transcriptional dynamics define lineage shifts in corticogenesis. EMBO J 2022; 41:e111132. [PMID: 36345783 PMCID: PMC9753470 DOI: 10.15252/embj.2022111132] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 09/09/2022] [Accepted: 09/26/2022] [Indexed: 11/11/2022] Open
Abstract
The cerebral cortex contains billions of neurons, and their disorganization or misspecification leads to neurodevelopmental disorders. Understanding how the plethora of projection neuron subtypes are generated by cortical neural stem cells (NSCs) is a major challenge. Here, we focused on elucidating the transcriptional landscape of murine embryonic NSCs, basal progenitors (BPs), and newborn neurons (NBNs) throughout cortical development. We uncover dynamic shifts in transcriptional space over time and heterogeneity within each progenitor population. We identified signature hallmarks of NSC, BP, and NBN clusters and predict active transcriptional nodes and networks that contribute to neural fate specification. We find that the expression of receptors, ligands, and downstream pathway components is highly dynamic over time and throughout the lineage implying differential responsiveness to signals. Thus, we provide an expansive compendium of gene expression during cortical development that will be an invaluable resource for studying neural developmental processes and neurodevelopmental disorders.
Collapse
Affiliation(s)
- Tanzila Mukhtar
- Department of BiomedicineUniversity of BaselBaselSwitzerland
| | - Jeremie Breda
- BiozentrumUniversity of BaselBaselSwitzerland
- Swiss Institute of Bioinformatics (SIB)BaselSwitzerland
| | - Manal A Adam
- Eli and Edythe Broad Center of Regeneration Medicine and Stem cell ResearchUniversity of California, San FranciscoSan FranciscoCAUSA
- Weill Institute for NeuroscienceSan FranciscoCAUSA
- Department of NeurologyUniversity of California, San FranciscoSan FranciscoCAUSA
| | - Marcelo Boareto
- Swiss Institute of Bioinformatics (SIB)BaselSwitzerland
- Computational Biology Group, D‐BSSEETH ZürichBaselSwitzerland
| | - Pascal Grobecker
- BiozentrumUniversity of BaselBaselSwitzerland
- Swiss Institute of Bioinformatics (SIB)BaselSwitzerland
| | - Zahra Karimaddini
- Swiss Institute of Bioinformatics (SIB)BaselSwitzerland
- Computational Biology Group, D‐BSSEETH ZürichBaselSwitzerland
| | - Alice Grison
- Department of BiomedicineUniversity of BaselBaselSwitzerland
| | - Katja Eschbach
- Department of Biosystems Science and EngineeringETH ZürichBaselSwitzerland
| | | | - Swen Vermeul
- Scientific IT ServicesETH ZürichZürichSwitzerland
| | | | - Mikhail Pachkov
- BiozentrumUniversity of BaselBaselSwitzerland
- Swiss Institute of Bioinformatics (SIB)BaselSwitzerland
| | - Corey C Harwell
- Eli and Edythe Broad Center of Regeneration Medicine and Stem cell ResearchUniversity of California, San FranciscoSan FranciscoCAUSA
- Weill Institute for NeuroscienceSan FranciscoCAUSA
- Department of NeurologyUniversity of California, San FranciscoSan FranciscoCAUSA
| | - Suzana Atanasoski
- Department of BiomedicineUniversity of BaselBaselSwitzerland
- Faculty of MedicineUniversity of ZürichZürichSwitzerland
| | - Christian Beisel
- Department of Biosystems Science and EngineeringETH ZürichBaselSwitzerland
| | - Dagmar Iber
- Swiss Institute of Bioinformatics (SIB)BaselSwitzerland
- Weill Institute for NeuroscienceSan FranciscoCAUSA
| | - Erik van Nimwegen
- BiozentrumUniversity of BaselBaselSwitzerland
- Swiss Institute of Bioinformatics (SIB)BaselSwitzerland
| | - Verdon Taylor
- Department of BiomedicineUniversity of BaselBaselSwitzerland
| |
Collapse
|
|
3
|
Hu L, Zhang L. Adult neural stem cells and schizophrenia. World J Stem Cells 2022; 14:219-230. [PMID: 35432739 PMCID: PMC8968214 DOI: 10.4252/wjsc.v14.i3.219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/18/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.
Collapse
Affiliation(s)
- Ling Hu
- Department of Laboratory Animal Science and Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center) and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
| |
Collapse
|
|
4
|
Kunii M, Noguchi Y, Yoshimura SI, Kanda S, Iwano T, Avriyanti E, Atik N, Sato T, Sato K, Ogawa M, Harada A. SNAP23 deficiency causes severe brain dysplasia through the loss of radial glial cell polarity. J Cell Biol 2021; 220:e201910080. [PMID: 33332551 PMCID: PMC7754684 DOI: 10.1083/jcb.201910080] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 08/23/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
In the developing brain, the polarity of neural progenitor cells, termed radial glial cells (RGCs), is important for neurogenesis. Intercellular adhesions, termed apical junctional complexes (AJCs), at the apical surface between RGCs are necessary for cell polarization. However, the mechanism by which AJCs are established remains unclear. Here, we show that a SNARE complex composed of SNAP23, VAMP8, and Syntaxin1B has crucial roles in AJC formation and RGC polarization. Central nervous system (CNS)-specific ablation of SNAP23 (NcKO) results in mice with severe hypoplasia of the neocortex and no hippocampus or cerebellum. In the developing NcKO brain, RGCs lose their polarity following the disruption of AJCs and exhibit reduced proliferation, increased differentiation, and increased apoptosis. SNAP23 and its partner SNAREs, VAMP8 and Syntaxin1B, are important for the localization of an AJC protein, N-cadherin, to the apical plasma membrane of RGCs. Altogether, SNARE-mediated localization of N-cadherin is essential for AJC formation and RGC polarization during brain development.
Collapse
Affiliation(s)
- Masataka Kunii
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
| | - Yuria Noguchi
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shin-ichiro Yoshimura
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Satoshi Kanda
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tomohiko Iwano
- Department of Anatomy and Cell Biology, Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Erda Avriyanti
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Dermatology and Venereology, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Nur Atik
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Biomedical Sciences, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Takashi Sato
- Laboratory of Developmental Biology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
| | - Ken Sato
- Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
| | | | - Akihiro Harada
- Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
| |
Collapse
|
|
5
|
Notch1 and Notch2 collaboratively maintain radial glial cells in mouse neurogenesis. Neurosci Res 2020; 170:122-132. [PMID: 33309869 DOI: 10.1016/j.neures.2020.11.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/26/2020] [Accepted: 11/27/2020] [Indexed: 11/22/2022]
Abstract
During mammalian corticogenesis, Notch signaling is essential to maintain neural stem cells called radial glial cells (RGCs) and the cortical architecture. Because the conventional knockout of either Notch1 or Notch2 causes a neuroepithelial loss prior to neurogenesis, their functional relationship in RGCs remain elusive. Here, we investigated the impacts of single knockout of Notch1 and Notch2 genes, and their conditional double knockout (DKO) on mouse corticogenesis. We demonstrated that Notch1 single knockout affected RGC maintenance in early to mid-neurogenesis whereas Notch2 knockout caused no apparent defect. In contrast, Notch2 plays a role in the RGC maintenance as Notch1 does at the late stage. Notch1 and Notch2 DKO resulted in the complete loss of RGCs, suggesting their cooperative function. We found that Notch activity in RGCs depends on the Notch gene dosage irrespective of Notch1 or Notch2 at late neurogenic stage, and that Notch1 and Notch2 have a similar activity, most likely due to a drastic increase in Notch2 transcription. Our results revealed that Notch1 has an essential role in establishing the RGC pool during the early stage, whereas Notch1 and Notch2 subsequently exhibit a comparable function for RGC maintenance and neurogenesis in the late neurogenic period in the mouse telencephalon.
Collapse
|
|
6
|
The Notch Ligand Jagged1 Is Required for the Formation, Maintenance, and Survival of Hensen's Cells in the Mouse Cochlea. J Neurosci 2020; 40:9401-9413. [PMID: 33127852 DOI: 10.1523/jneurosci.1192-20.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 10/16/2020] [Accepted: 10/23/2020] [Indexed: 01/09/2023] Open
Abstract
During cochlear development, the Notch ligand JAGGED 1 (JAG1) plays an important role in the specification of the prosensory region, which gives rise to sound-sensing hair cells and neighboring supporting cells (SCs). While JAG1's expression is maintained in SCs through adulthood, the function of JAG1 in SC development is unknown. Here, we demonstrate that JAG1 is essential for the formation and maintenance of Hensen's cells, a highly specialized SC subtype located at the edge of the auditory epithelium. Using Sox2 CreERT2/+::Jag1loxP/loxP mice of both genders, we show that Jag1 deletion at the onset of differentiation, at embryonic day 14.5, disrupted Hensen's cell formation. Similar loss of Hensen's cells was observed when Jag1 was deleted after Hensen's cell formation at postnatal day (P) 0/P1 and fate-mapping analysis revealed that in the absence of Jag1, some Hensen's cells die, but others convert into neighboring Claudius cells. In support of a role for JAG1 in cell survival, genes involved in mitochondrial function and protein synthesis were downregulated in the sensory epithelium of P0 cochlea lacking Jag1 Finally, using Fgfr3-iCreERT2 ::Jag1loxP/loxP mice to delete Jag1 at P0, we observed a similar loss of Hensen's cells and found that adult Jag1 mutant mice have hearing deficits at the low-frequency range.SIGNIFICANCE STATEMENT Hensen's cells play an essential role in the development and homeostasis of the cochlea. Defects in the biophysical or functional properties of Hensen's cells have been linked to auditory dysfunction and hearing loss. Despite their importance, surprisingly little is known about the molecular mechanisms that guide their development. Morphologic and fate-mapping analyses in our study revealed that, in the absence of the Notch ligand JAGGED1, Hensen's cells died or converted into Claudius cells, which are specialized epithelium-like cells outside the sensory epithelium. Confirming a link between JAGGED1 and cell survival, transcriptional profiling showed that JAGGED1 maintains genes critical for mitochondrial function and tissue homeostasis. Finally, auditory phenotyping revealed that JAGGED1's function in supporting cells is necessary for low-frequency hearing.
Collapse
|
|
7
|
Son AI, Mohammad S, Sasaki T, Ishii S, Yamashita S, Hashimoto-Torii K, Torii M. Dual Role of Rbpj in the Maintenance of Neural Progenitor Cells and Neuronal Migration in Cortical Development. Cereb Cortex 2020; 30:6444-6457. [PMID: 32780108 DOI: 10.1093/cercor/bhaa206] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 06/09/2020] [Accepted: 07/06/2020] [Indexed: 12/30/2022] Open
Abstract
The development of the cerebral cortex is directed by a series of methodically precise events, including progenitor cell proliferation, neural differentiation, and cell positioning. Over the past decade, many studies have demonstrated the critical contributions of Notch signaling in neurogenesis, including that in the developing telencephalon. However, in vivo evidence for the role of Notch signaling in cortical development still remains limited partly due to the redundant functions of four mammalian Notch paralogues and embryonic lethality of the knockout mice. Here, we utilized the conditional deletion and in vivo gene manipulation of Rbpj, a transcription factor that mediates signaling by all four Notch receptors, to overcome these challenges and examined the specific roles of Rbpj in cortical development. We report severe structural abnormalities in the embryonic and postnatal cerebral cortex in Rbpj conditional knockout mice, which provide strong in vivo corroboration of previously reported functions of Notch signaling in neural development. Our results also provide evidence for a novel dual role of Rbpj in cell type-specific regulation of two key developmental events in the cerebral cortex: the maintenance of the undifferentiated state of neural progenitor cells, and the radial and tangential allocation of neurons, possibly through stage-dependent differential regulation of Ngn1.
Collapse
Affiliation(s)
- Alexander I Son
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Shahid Mohammad
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Toru Sasaki
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Seiji Ishii
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Satoshi Yamashita
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Kazue Hashimoto-Torii
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC 20010, USA.,Department of Pediatrics, Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| | - Masaaki Torii
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC 20010, USA.,Department of Pediatrics, Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20052, USA
| |
Collapse
|
|
8
|
Epigenetic Regulation of Notch Signaling During Drosophila Development. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1218:59-75. [PMID: 32060871 DOI: 10.1007/978-3-030-34436-8_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Notch signaling exerts multiple important functions in various developmental processes, including cell differentiation and cell proliferation, while mis-regulation of this pathway results in a variety of complex diseases, such as cancer and developmental defects. The simplicity of the Notch pathway in Drosophila melanogaster, in combination with the availability of powerful genetics, makes this an attractive model for studying the fundamental mechanisms of how Notch signaling is regulated and how it functions in various cellular contexts. Recently, increasing evidence for epigenetic control of Notch signaling reveals the intimate link between epigenetic regulators and Notch signaling pathway. In this chapter, we summarize the research advances of Notch and CAF-1 in Drosophila development and the epigenetic regulation mechanisms of Notch signaling activity by CAF-1 as well as other epigenetic modification machineries, which enables Notch to orchestrate different biological inputs and outputs in specific cellular contexts.
Collapse
|
|
9
|
Fleming T, Balderas-Márquez JE, Epardo D, Ávila-Mendoza J, Carranza M, Luna M, Harvey S, Arámburo C, Martínez-Moreno CG. Growth Hormone Neuroprotection Against Kainate Excitotoxicity in the Retina is Mediated by Notch/PTEN/Akt Signaling. Invest Ophthalmol Vis Sci 2020; 60:4532-4547. [PMID: 31675424 DOI: 10.1167/iovs.19-27473] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose In the retina, growth hormone (GH) promotes axonal growth, synaptic restoration, and protective actions against excitotoxicity. Notch signaling pathway is critical for neural development and participates in the retinal neuroregenerative process. We investigated the interaction of GH with Notch signaling pathway during its neuroprotective effect against excitotoxic damage in the chicken retina. Methods Kainate (KA) was used as excitotoxic agent and changes in the mRNA expression of several signaling markers were determined by qPCR. Also, changes in phosphorylation and immunoreactivity were determined by Western blotting. Histology and immunohistochemistry were performed for morphometric analysis. Overexpression of GH was performed in the quail neuroretinal-derived immortalized cell line (QNR/D) cell line. Exogenous GH was administered to retinal primary cell cultures to study the activation of signaling pathways. Results KA disrupted the retinal cytoarchitecture and induced significant cell loss in several retinal layers, but the coaddition of GH effectively prevented these adverse effects. We showed that GH upregulates the Notch signaling pathway during neuroprotection leading to phosphorylation of the PI3K/Akt signaling pathways through downregulation of PTEN. In contrast, cotreatment of GH with the Notch signaling inhibitor, DAPT, prevented its neuroprotective effect against KA. We identified binding sites in Notch1 and Notch2 genes for STAT5. Also, GH prevented Müller cell transdifferentiation and downregulated Sox2, FGF2, and PCNA after cotreatment with KA. Additionally, GH modified TNF receptors immunoreactivity suggesting anti-inflammatory actions. Conclusions Our data indicate that the neuroprotective effects of GH against KA injury in the retina are mediated through the regulation of Notch signaling. Additionally, anti-inflammatory and antiproliferative effects were observed.
Collapse
Affiliation(s)
- Thomas Fleming
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México.,Department of Physiology, University of Alberta, Edmonton, Canada
| | - Jerusa E Balderas-Márquez
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - David Epardo
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - José Ávila-Mendoza
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States
| | - Martha Carranza
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - Maricela Luna
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - Steve Harvey
- Department of Physiology, University of Alberta, Edmonton, Canada
| | - Carlos Arámburo
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - Carlos G Martínez-Moreno
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| |
Collapse
|
|
10
|
Kim S, Lee M, Choi YK. The Role of a Neurovascular Signaling Pathway Involving Hypoxia-Inducible Factor and Notch in the Function of the Central Nervous System. Biomol Ther (Seoul) 2020; 28:45-57. [PMID: 31484285 PMCID: PMC6939687 DOI: 10.4062/biomolther.2019.119] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/06/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022] Open
Abstract
In the neurovascular unit, the neuronal and vascular systems communicate with each other. O2 and nutrients, reaching endothelial cells (ECs) through the blood stream, spread into neighboring cells, such as neural stem cells, and neurons. The proper function of neural circuits in adults requires sufficient O2 and glucose for their metabolic demands through angiogenesis. In a central nervous system (CNS) injury, such as glioma, Parkinson’s disease, and Alzheimer’s disease, damaged ECs can contribute to tissue hypoxia and to the consequent disruption of neuronal functions and accelerated neurodegeneration. This review discusses the current evidence regarding the contribution of oxygen deprivation to CNS injury, with an emphasis on hypoxia-inducible factor (HIF)-mediated pathways and Notch signaling. Additionally, it focuses on adult neurological functions and angiogenesis, as well as pathological conditions in the CNS. Furthermore, the functional interplay between HIFs and Notch is demonstrated in pathophysiological conditions.
Collapse
Affiliation(s)
- Seunghee Kim
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Minjae Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Yoon Kyung Choi
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| |
Collapse
|
|
11
|
Notch Signaling and Embryonic Development: An Ancient Friend, Revisited. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1218:9-37. [PMID: 32060869 DOI: 10.1007/978-3-030-34436-8_2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The evolutionary highly conserved Notch pathway, which first developed during evolution in metazoans and was first discovered in fruit flies (Drosophila melanogaster), governs many core processes including cell fate decisions during embryonic development. A huge mountain of scientific evidence convincingly demonstrates that Notch signaling represents one of the most important pathways that regulate embryogenesis from sponges, roundworms, Drosophila melanogaster, and mice to humans. In this review, we give a brief introduction on how Notch orchestrates the embryonic development of several selected tissues, summarizing some of the most relevant findings in the central nervous system, skin, kidneys, liver, pancreas, inner ear, eye, skeleton, heart, and vascular system.
Collapse
|
|
12
|
Ng CL, Qian Y, Schulz C. Notch and Delta are required for survival of the germline stem cell lineage in testes of Drosophila melanogaster. PLoS One 2019; 14:e0222471. [PMID: 31513679 PMCID: PMC6742463 DOI: 10.1371/journal.pone.0222471] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 08/29/2019] [Indexed: 01/27/2023] Open
Abstract
In all metazoan species, sperm is produced from germline stem cells. These self-renew and produce daughter cells that amplify and differentiate dependent on interactions with somatic support cells. In the male gonad of Drosophila melanogaster, the germline and somatic cyst cells co-differentiate as cysts, an arrangement in which the germline is completely enclosed by cytoplasmic extensions from the cyst cells. Notch is a developmentally relevant receptor in a pathway requiring immediate proximity with the signal sending cell. Here, we show that Notch is expressed in the cyst cells of wild-type testes. Notch becomes activated in the transition zone, an apical area of the testes in which the cyst cells express stage-specific transcription factors and the enclosed germline finalizes transit-amplifying divisions. Reducing the ligand Delta from the germline cells via RNA-Interference or reducing the receptor Notch from the cyst cells via CRISPR resulted in cell death concomitant with loss of germline cells from the transition zone. This shows that Notch signaling is essential for the survival of the germline stem cell lineage.
Collapse
Affiliation(s)
- Chun L. Ng
- University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Yue Qian
- University of North Georgia, Department of Biology, Oakwood, Georgia, United States of America
| | - Cordula Schulz
- University of Georgia, Department of Cellular Biology, Athens, Georgia, United States of America
| |
Collapse
|
|
13
|
Abstract
Neurogenesis is the process of forming neurons and is essential during vertebrate development to produce most of the neurons of the adult brain. However, neurogenesis continues throughout life at distinct locations in the vertebrate brain. Neural stem cells (NSCs) are the origin of both embryonic and adult neurogenesis, but their activity and fate are tightly regulated by their local milieu or niche. In this chapter, we will discuss the role of Notch signaling in the control of neurogenesis and regeneration in the embryo and adult. Notch-dependence is a common feature among NSC populations, we will discuss how differences in Notch signaling might contribute to heterogeneity among adult NSCs. Understanding the fate of multiple NSC populations with distinct functions could be important for effective brain regeneration.
Collapse
|
|
14
|
Sadoul R, Laporte MH, Chassefeyre R, Chi KI, Goldberg Y, Chatellard C, Hemming FJ, Fraboulet S. The role of ESCRT during development and functioning of the nervous system. Semin Cell Dev Biol 2017; 74:40-49. [PMID: 28811263 DOI: 10.1016/j.semcdb.2017.08.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 07/21/2017] [Accepted: 08/04/2017] [Indexed: 12/12/2022]
Abstract
The endosomal sorting complex required for transport (ESCRT) is made of subcomplexes (ESCRT 0-III), crucial to membrane remodelling at endosomes, nuclear envelope and cell surface. ESCRT-III shapes membranes and in most cases cooperates with the ATPase VPS4 to mediate fission of membrane necks from the inside. The first ESCRT complexes mainly serve to catalyse the formation of ESCRT-III but can be bypassed by accessory proteins like the Alg-2 interacting protein-X (ALIX). In the nervous system, ALIX/ESCRT controls the survival of embryonic neural progenitors and later on the outgrowth and pruning of axons and dendrites, all necessary steps to establish a functional brain. In the adult brain, ESCRTs allow the endosomal turn over of synaptic vesicle proteins while stable ESCRT complexes might serve as scaffolds for the postsynaptic parts. The necessity of ESCRT for the harmonious function of the brain has its pathological counterpart, the mutations in CHMP2B of ESCRT-III giving rise to several neurodegenerative diseases.
Collapse
Affiliation(s)
- Rémy Sadoul
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France; Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
| | - Marine H Laporte
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France; Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Romain Chassefeyre
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France; Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Kwang Il Chi
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France; Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Yves Goldberg
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France; Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Christine Chatellard
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France; Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Fiona J Hemming
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France; Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Sandrine Fraboulet
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France; Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| |
Collapse
|
|
15
|
Laporte MH, Chatellard C, Vauchez V, Hemming FJ, Deloulme JC, Vossier F, Blot B, Fraboulet S, Sadoul R. Alix is required during development for normal growth of the mouse brain. Sci Rep 2017; 7:44767. [PMID: 28322231 PMCID: PMC5359572 DOI: 10.1038/srep44767] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 02/14/2017] [Indexed: 12/20/2022] Open
Abstract
Alix (ALG-2 interacting protein X) drives deformation and fission of endosomal and cell surface membranes and thereby intervenes in diverse biological processes including cell proliferation and apoptosis. Using embryonic fibroblasts of Alix knock-out mice, we recently demonstrated that Alix is required for clathrin-independent endocytosis. Here we show that mice lacking Alix suffer from severe reduction in the volume of the brain which affects equally all regions examined. The cerebral cortex of adult animals shows normal layering but is reduced in both medio-lateral length and thickness. Alix controls brain size by regulating its expansion during two distinct developmental stages. Indeed, embryonic surface expansion of the Alix ko cortex is reduced because of the loss of neural progenitors during a transient phase of apoptosis occurring between E11.5 and E12.5. Subsequent development of the Alix ko cortex occurs normally until birth, when Alix is again required for the post-natal radial expansion of the cortex through its capacity to allow proper neurite outgrowth. The need of Alix for both survival of neural progenitor cells and neurite outgrowth is correlated with its role in clathrin-independent endocytosis in neural progenitors and at growth cones. Thus Alix-dependent, clathrin independent endocytosis is essential for controlling brain size.
Collapse
Affiliation(s)
- Marine H. Laporte
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France
- Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Christine Chatellard
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France
- Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Victoria Vauchez
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France
- Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Fiona J. Hemming
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France
- Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Jean-Christophe Deloulme
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France
- Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Frédérique Vossier
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France
- Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Béatrice Blot
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France
- Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Sandrine Fraboulet
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France
- Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| | - Rémy Sadoul
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France
- Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France
| |
Collapse
|
|
16
|
Abstract
Parkin, an E3 ubiquitin ligase, is the most frequently mutated gene in hereditary Parkinson's disease. Inactivation of Parkin leads to impairment of the ubiquitin-proteasome system, resulting in the accumulation of misfolded or aggregated proteins and ensuing neurodegeneration. In this study, we show that Parkin positively regulates the Notch1 signaling pathway. Overexpression of Parkin stabilized Notch1-IC protein levels, whereas knockdown of Parkin decreased Notch1-IC protein stability. Notably, overexpression of Parkin disrupted oxidative stress-induced apoptosis in neuronal cells. However, knockdown of Notch1 inhibited Parkin-induced neuronal cell survival. Together, these results indicate that Parkin is a novel regulator of the Notch1 signaling pathway, which promotes neuronal cell survival.
Collapse
|
|
17
|
Li Y, Tzatzalos E, Kwan KY, Grumet M, Cai L. Transcriptional Regulation of Notch1 Expression by Nkx6.1 in Neural Stem/Progenitor Cells during Ventral Spinal Cord Development. Sci Rep 2016; 6:38665. [PMID: 27924849 PMCID: PMC5141430 DOI: 10.1038/srep38665] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 11/14/2016] [Indexed: 12/22/2022] Open
Abstract
Notch1 signaling plays a critical role in maintaining and determining neural stem/progenitor cell (NSPC) fate, yet the transcriptional mechanism controlling Notch1 specific expression in NSPCs remains incomplete. Here, we show transcription factor Nkx6.1 interacts with a cis-element (CR2, an evolutionarily conserved non-coding fragment in the second intron of Notch1 locus) and regulates the expression of Notch1 in ventral NSPCs of the developing spinal cord. We show that the Notch1 expression is modulated by the interaction of Nkx6.1 with a 139 bp enhancer sequence within CR2. Knockdown or overexpression of Nkx6.1 leads to down- or up-regulated Notch1 expression, respectively. In CR2-GFP transgenic mouse, GFP expression was found prominent in the ventricular zone and neural progenitor cells from embryonic day 9.5 to postnatal day 7. GFP+ cells were mainly neural progenitors for interneurons and not for motoneurons or glial cells. Moreover, GFP expression persisted in a subset of ependymal cells in the adult spinal cord, suggesting that CR2 is active in both embryonic and adult NSPCs. Together our data reveal a novel mechanism of Notch1 transcriptional regulation in the ventral spinal cord by Nkx6.1 via its binding with Notch1 enhancer CR2 during embryonic development.
Collapse
Affiliation(s)
- Ying Li
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA
| | - Evangeline Tzatzalos
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA
| | - Kelvin Y Kwan
- W.M. Keck Center for Collaborative Neuroscience, Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA
| | - Martin Grumet
- W.M. Keck Center for Collaborative Neuroscience, Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA
| | - Li Cai
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA
| |
Collapse
|
|
18
|
Bonini SA, Mastinu A, Maccarinelli G, Mitola S, Premoli M, La Rosa LR, Ferrari-Toninelli G, Grilli M, Memo M. Cortical Structure Alterations and Social Behavior Impairment in p50-Deficient Mice. Cereb Cortex 2016; 26:2832-49. [PMID: 26946128 PMCID: PMC4869818 DOI: 10.1093/cercor/bhw037] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Alterations in genes that regulate neurodevelopment can lead to cortical malformations, resulting in malfunction during postnatal life. The NF-κB pathway has a key role during neurodevelopment by regulating the maintenance of the neural progenitor cell pool and inhibiting neuronal differentiation. In this study, we evaluated whether mice lacking the NF-κB p50 subunit (KO) present alterations in cortical structure and associated behavioral impairment. We found that, compared with wild type (WT), KO mice at postnatal day 2 present an increase in radial glial cells, an increase in Reelin protein expression levels, in addition to an increase of specific layer thickness. Moreover, adult KO mice display abnormal columnar organization in the somatosensory cortex, a specific decrease in somatostatin- and parvalbumin-expressing interneurons, altered neurite orientation, and a decrease in Synapsin I protein levels. Concerning behavior, KO mice, in addition to an increase in locomotor and exploratory activity, display impairment in social behaviors, with a reduction in social interaction. Finally, we found that risperidone treatment decreased hyperactivity of KO mice, but had no effect on defective social interaction. Altogether, these data add complexity to a growing body of data, suggesting a link between dysregulation of the NF-κB pathway and neurodevelopmental disorders pathogenesis.
Collapse
Affiliation(s)
- Sara Anna Bonini
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Andrea Mastinu
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Giuseppina Maccarinelli
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Stefania Mitola
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Marika Premoli
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Luca Rosario La Rosa
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | | | - Mariagrazia Grilli
- Laboratory of Neuroplasticity, Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy
| | - Maurizio Memo
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| |
Collapse
|
|
19
|
Azizidoost S, Bavarsad MS, Bavarsad MS, Shahrabi S, Jaseb K, Rahim F, Shahjahani M, Saba F, Ghorbani M, Saki N. The role of notch signaling in bone marrow niche. Hematology 2015; 20:93-103. [PMID: 24724873 DOI: 10.1179/1607845414y.0000000167] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025] Open
Abstract
OBJECTIVE Bone marrow (BM) niche is a three-dimensional structure composed of a series of cells and it is one of the most controversial topics in hematological malignancies, leukemia, and even metastasis. Here, we review the relationship between Notch signaling and different fates of stem cells and other BM niche cells. METHODS Relevant English-language literature were searched and retrieved from PubMed (2000-2013) using the terms Notch signaling, BM niche, and microRNAs (miRNAs). DISCUSSION Notch signaling pathway is a signaling system involved in cellular processes such as proliferation, differentiation, and apoptosis. The notch signaling pathway components are associated with interaction between leukemic, metastatic, and normal cells and their microenvironment. miRNAs play an important role in expression and regulation of signaling molecules. It is necessary to evaluate the relationship between aberrant miRNA expression and notch signaling such as miR-128 and miR-30 in glioma and angiogenesis with notch signaling, respectively. CONCLUSIONS Characterizing malignant cells and future studies focus on better understanding the variety of cancers and apoptosis with activated Notch signaling pathway, may remain promising this signaling system as a safe and effective therapeutic target.
Collapse
|
|
20
|
Cell death in development: Signaling pathways and core mechanisms. Semin Cell Dev Biol 2015; 39:12-9. [PMID: 25668151 DOI: 10.1016/j.semcdb.2015.02.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 01/22/2015] [Accepted: 02/02/2015] [Indexed: 11/20/2022]
Abstract
Programmed cell death eliminates unneeded and dangerous cells in a timely and effective manner during development. In this review, we examine the role cell death plays during development in worms, flies and mammals. We discuss signaling pathways that regulate developmental cell death, and describe how they communicate with the core cell death pathways. In most organisms, the majority of developmental cell death is seen in the nervous system. Therefore we focus on what is known about the regulation of developmental cell death in this tissue. Understanding how the cell death is regulated during development may provide insight into how this process can be manipulated in the treatment of disease.
Collapse
|
|
21
|
Annenkov A. Receptor tyrosine kinase (RTK) signalling in the control of neural stem and progenitor cell (NSPC) development. Mol Neurobiol 2013; 49:440-71. [PMID: 23982746 DOI: 10.1007/s12035-013-8532-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 08/09/2013] [Indexed: 01/04/2023]
Abstract
Important developmental responses are elicited in neural stem and progenitor cells (NSPC) by activation of the receptor tyrosine kinases (RTK), including the fibroblast growth factor receptors, epidermal growth factor receptor, platelet-derived growth factor receptors and insulin-like growth factor receptor (IGF1R). Signalling through these RTK is necessary and sufficient for driving a number of developmental processes in the central nervous system. Within each of the four RTK families discussed here, receptors are activated by sets of ligands that do not cross-activate receptors of the other three families, and therefore, their activation can be independently regulated by ligand availability. These RTK pathways converge on a conserved core of signalling molecules, but differences between the receptors in utilisation of signalling molecules and molecular adaptors for intracellular signal propagation become increasingly apparent. Intracellular inhibitors of RTK signalling are widely involved in the regulation of developmental signalling in NSPC and often determine developmental outcomes of RTK activation. In addition, cellular responses of NSPC to the activation of a given RTK may be significantly modulated by signal strength. Cellular propensity to respond also plays a role in developmental outcomes of RTK signalling. In combination, these mechanisms regulate the balance between NSPC maintenance and differentiation during development and in adulthood. Attribution of particular developmental responses of NSPC to specific pathways of RTK signalling becomes increasingly elucidated. Co-activation of several RTK in developing NSPC is common, and analysis of co-operation between their signalling pathways may advance knowledge of RTK role in NSPC development.
Collapse
Affiliation(s)
- Alexander Annenkov
- Bone and Joint Research Unit, William Harvey Research Institute, Bart's and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK,
| |
Collapse
|
|
22
|
Yang K, Banerjee S, Proweller A. Regulation of pre-natal circle of Willis assembly by vascular smooth muscle Notch signaling. Dev Biol 2013; 381:107-20. [PMID: 23769842 DOI: 10.1016/j.ydbio.2013.06.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Revised: 05/30/2013] [Accepted: 06/06/2013] [Indexed: 12/16/2022]
Abstract
The circle of Willis (cW) is a major arterial collateral structure interconnecting hemispheric circulation within the brain, and in humans, anatomical variation of the cW is linked to stroke risk. Our prior studies on adult mice deficient in vascular smooth muscle cell (vSMC) Notch signaling revealed altered cerebroarterial maturation and patterning, including an anatomically incompetent cW similar to human variants. However, a developmental dependency on Notch signaling for cW formation in this model remained uncharacterized. Through temporospatial embryonic analyses, we now demonstrate that cW assembly is a pre-natal process highly sensitive to vSMC Notch signals, whose absence results in delayed nascent vascular plexus formation and under-development of the cW including the key anterior communicating artery (AComA) interconnecting anterior forebrain circulation. Mutant embryos additionally feature reduced vSMC coverage, non-uniform calibers and asymmetric branching at bifurcations of the major proximal cerebral arteries. At the cellular level, a notable reduction in vascular endothelial cell proliferation exists in the region of AComA assembly despite the presence of Vegfa. Furthermore, Notch signaling-deficient vSMCs in developing cerebral vessels feature reduced Pdgfrβ and Jagged1 levels and impaired proliferation. These collective findings in the embryonic brain support studies in adult animals demonstrating a reliance on intact vSMC Notch signaling for optimal neovascular responses to angiogenic stimuli. Importantly, the new data provide unique insights into the native formation of the cW and underscore a pioneering developmental role for vSMC Notch signaling in regulating temporospatial assembly of the clinically relevant cW.
Collapse
Affiliation(s)
- Ke Yang
- Case Cardiovascular Research Institute and University Hospitals Harrington Heart and Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | | | | |
Collapse
|
|
23
|
Shulha HP, Cheung I, Guo Y, Akbarian S, Weng Z. Coordinated cell type-specific epigenetic remodeling in prefrontal cortex begins before birth and continues into early adulthood. PLoS Genet 2013; 9:e1003433. [PMID: 23593028 PMCID: PMC3623761 DOI: 10.1371/journal.pgen.1003433] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Accepted: 02/20/2013] [Indexed: 11/21/2022] Open
Abstract
Development of prefrontal and other higher-order association cortices is associated with widespread changes in the cortical transcriptome, particularly during the transitions from prenatal to postnatal development, and from early infancy to later stages of childhood and early adulthood. However, the timing and longitudinal trajectories of neuronal gene expression programs during these periods remain unclear in part because of confounding effects of concomitantly occurring shifts in neuron-to-glia ratios. Here, we used cell type–specific chromatin sorting techniques for genome-wide profiling of a histone mark associated with transcriptional regulation—H3 with trimethylated lysine 4 (H3K4me3)—in neuronal chromatin from 31 subjects from the late gestational period to 80 years of age. H3K4me3 landscapes of prefrontal neurons were developmentally regulated at 1,157 loci, including 768 loci that were proximal to transcription start sites. Multiple algorithms consistently revealed that the overwhelming majority and perhaps all of developmentally regulated H3K4me3 peaks were on a unidirectional trajectory defined by either rapid gain or loss of histone methylation during the late prenatal period and the first year after birth, followed by similar changes but with progressively slower kinetics during early and later childhood and only minimal changes later in life. Developmentally downregulated H3K4me3 peaks in prefrontal neurons were enriched for Paired box (Pax) and multiple Signal Transducer and Activator of Transcription (STAT) motifs, which are known to promote glial differentiation. In contrast, H3K4me3 peaks subject to a progressive increase in maturing prefrontal neurons were enriched for activating protein-1 (AP-1) recognition elements that are commonly associated with activity-dependent regulation of neuronal gene expression. We uncovered a developmental program governing the remodeling of neuronal histone methylation landscapes in the prefrontal cortex from the late prenatal period to early adolescence, which is linked to cis-regulatory sequences around transcription start sites. Prolonged maturation of the human cerebral cortex, which extends into the third decade of life, is critical for proper development of executive functions such as higher-order problem-solving and complex cognition. Little is known about changes of post-mitotic neurons during this prolonged maturation period, including changes in epigenetic regulation, and more broadly, in genome organization and function. Such knowledge is critical for a deeper understanding of human development, cognitive abilities, and psychiatric diseases. Here, we identify 1,157 genomic loci in neuronal cells from the prefrontal cortex that show developmental changes in a chromatin mark, histone H3 trimethylated at lysine 4 (H3K4me3), which has been associated with regulation of gene expression. Interestingly, the overwhelming majority of these developmentally regulated H3K4me3 peaks were defined by rapid gain or loss of histone methylation during the late prenatal period and the first year after birth, followed by slower changes during early and later childhood and minimal changes thereafter. The genomic sequences showing these dynamic changes in H3K4me3 were enriched with distinct transcription factor motifs. Our findings suggest that there is highly regulated, pre-programmed remodeling of neuronal histone methylation landscapes in the human brain that begins before birth and continues into adolescence.
Collapse
Affiliation(s)
- Hennady P. Shulha
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Iris Cheung
- Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Yin Guo
- Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Schahram Akbarian
- Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
- Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, New York, United States of America
- * E-mail: (SA); (ZW)
| | - Zhiping Weng
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
- * E-mail: (SA); (ZW)
| |
Collapse
|
|
24
|
Li Y, Hibbs MA, Gard AL, Shylo NA, Yun K. Genome-wide analysis of N1ICD/RBPJ targets in vivo reveals direct transcriptional regulation of Wnt, SHH, and hippo pathway effectors by Notch1. Stem Cells 2012; 30:741-52. [PMID: 22232070 DOI: 10.1002/stem.1030] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The Notch pathway plays a pivotal role in regulating cell fate decisions in many stem cell systems. However, the full repertoire of Notch target genes in vivo and the mechanisms through which this pathway activity is integrated with other signaling pathways are largely unknown. Here, we report a transgenic mouse in which the activation of the Notch pathway massively expands the neural stem cell (NSC) pool in a cell context-dependent manner. Using this in vivo system, we identify direct targets of RBPJ/N1ICD in cortical NSCs at a genome-wide level through combined ChIP-Seq and transcriptome analyses. Through a highly conservative analysis of these datasets, we identified 98 genes that are directly regulated by N1ICD/RPBJ in vivo. These include many transcription factors that are known to be critical for NSC self-renewal (Sox2, Pax6, Tlx, and Id4) and the transcriptional effectors of the Wnt, SHH, and Hippo pathways, TCF4, Gli2, Gli3, Yap1, and Tead2. Since little is known about the function of the Hippo-Yap pathway in NSCs, we analyzed Yap1 expression and function in NSCs. We show that Yap1 expression is restricted to the stem cell compartment in the developing forebrain and that its expression is sufficient to rescue Notch pathway inhibition in NSC self-renewal assays. Together, results of this study reveal a previously underappreciated complexity and breadth of Notch1 targets in vivo and show direct interaction between Notch and Hippo-Yap pathways in NSCs.
Collapse
Affiliation(s)
- Yaochen Li
- The Jackson Laboratory, Bar Harbor, Maine, USA
| | | | | | | | | |
Collapse
|
|
25
|
Kanungo J, Cuevas E, Ali SF, Paule MG. Ketamine induces motor neuron toxicity and alters neurogenic and proneural gene expression in zebrafish. J Appl Toxicol 2011; 33:410-7. [PMID: 22045596 DOI: 10.1002/jat.1751] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 09/06/2011] [Accepted: 09/06/2011] [Indexed: 01/06/2023]
Abstract
Ketamine, a noncompetitive antagonist of N-methyl-d-aspartate-type glutamate receptors, is a pediatric anesthetic that has been shown to be neurotoxic in rodents and nonhuman primates when administered during the brain growth spurt. Recently, the zebrafish has become an attractive model for toxicity assays, in part because the predictive capability of the zebrafish model, with respect to chemical effects, compares well with that from mammalian models. In the transgenic (hb9:GFP) embryos used in this study, green fluorescent protein (GFP) is expressed in the motor neurons, facilitating the visualization and analysis of motor neuron development in vivo. In order to determine whether ketamine induces motor neuron toxicity in zebrafish, embryos of these transgenic fish were treated with different concentrations of ketamine (0.5 and 2.0 mm). For ketamine exposures lasting up to 20 h, larvae showed no gross morphological abnormalities. Analysis of GFP-expressing motor neurons in the live embryos, however, revealed that 2.0 mm ketamine adversely affected motor neuron axon length and decreased cranial and motor neuron populations. Quantitative reverse transcriptase-polymerase chain reaction analysis demonstrated that ketamine down-regulated the motor neuron-inducing zinc finger transcription factor Gli2b and the proneural gene NeuroD even at 0.5 mm concentration, while up-regulating the expression of the proneural gene Neurogenin1 (Ngn1). Expression of the neurogenic gene, Notch1a, was suppressed, indicating that neuronal precursor generation from uncommitted cells was favored. These results suggest that ketamine is neurotoxic to motor neurons in zebrafish and possibly affects the differentiating/differentiatedneurons rather than neuronal progenitors. Published 2011. This article is a US Government work and is in the public domain in the USA.
Collapse
Affiliation(s)
- Jyotshna Kanungo
- Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
| | | | | | | |
Collapse
|
|
26
|
Abstract
Cerebral cortical progenitor cells can be classified into several different types, and each progenitor type integrates cell-intrinsic and cell-extrinsic cues to regulate neurogenesis. On one hand, cell-intrinsic mechanisms that depend upon appropriate apical-basal polarity are established by adherens junctions and apical complex proteins and are particularly important in progenitors with apical processes contacting the lateral ventricle. The apical protein complexes themselves are concentrated at the ventricular surface, and apical complex proteins regulate mitotic spindle orientation and cell fate. On the other hand, remarkably little is known about how cell-extrinsic cues signal to progenitors and couple with cell-intrinsic mechanisms to instruct neurogenesis. Recent research shows that the cerebrospinal fluid, which contacts apical progenitors at the ventricular surface and bathes the apical complex of these cells, provides growth- and survival-promoting cues for neural progenitor cells in developing and adult brain. This review addresses how the apical-basal polarity of progenitor cells regulates cell fate and allows progenitors to sample diffusible signals distributed by the cerebrospinal fluid. We also review several classes of signaling factors that the cerebrospinal fluid distributes to the developing brain to instruct neurogenesis.
Collapse
Affiliation(s)
- Maria K Lehtinen
- Division of Genetics, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
| | | |
Collapse
|
|
27
|
Ables JL, Breunig JJ, Eisch AJ, Rakic P. Not(ch) just development: Notch signalling in the adult brain. Nat Rev Neurosci 2011; 12:269-83. [PMID: 21505516 DOI: 10.1038/nrn3024] [Citation(s) in RCA: 325] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The Notch pathway is often regarded as a developmental pathway, but components of Notch signalling are expressed and active in the adult brain. With the advent of more sophisticated genetic manipulations, evidence has emerged that suggests both conserved and novel roles for Notch signalling in the adult brain. Not surprisingly, Notch is a key regulator of adult neural stem cells, but it is increasingly clear that Notch signalling also has roles in the regulation of migration, morphology, synaptic plasticity and survival of immature and mature neurons. Understanding the many functions of Notch signalling in the adult brain, and its dysfunction in neurodegenerative disease and malignancy, is crucial to the development of new therapeutics that are centred around this pathway.
Collapse
Affiliation(s)
- Jessica L Ables
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | | | | | | |
Collapse
|
|
28
|
From the vascular microenvironment to neurogenesis. Brain Res Bull 2011; 84:1-7. [DOI: 10.1016/j.brainresbull.2010.09.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Revised: 09/08/2010] [Accepted: 09/09/2010] [Indexed: 12/22/2022]
|
|
29
|
Julian E, Hallahan AR, Wainwright BJ. RBP-J is not required for granule neuron progenitor development and medulloblastoma initiated by Hedgehog pathway activation in the external germinal layer. Neural Dev 2010; 5:27. [PMID: 20950430 PMCID: PMC2972267 DOI: 10.1186/1749-8104-5-27] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Accepted: 10/15/2010] [Indexed: 11/25/2022] Open
Abstract
Background The Notch signalling pathway plays crucial roles in neural development, functioning by preventing premature differentiation and promotion of glial cell fates. In the developing cerebellum Notch pathway components are expressed in granule neuron progenitors of the external germinal layer (EGL) but the precise function of Notch in these cells is unclear. The Hedgehog pathway is also crucial in cerebellar development, mainly via control of the cell cycle, and persistent activation of the pathways leads to the cerebellar tumour medulloblastoma. Interactions between Hedgehog and Notch have been reported in normal brain development as well as in Hedgehog pathway induced medulloblastoma but the molecular details of this interaction are not known and we investigate here the role of Notch signalling in the development of the EGL and the intersection between the two pathways in cerebellar granule neuron progenitors and in medulloblastoma. Results RBP-J is the major downstream effector of all four mammalian Notch receptors and the RBP-J conditional mouse facilitates inactivation of canonical Notch signals. Patched1 is a negative regulator of Hedgehog signalling and the Patched1 conditional mouse is widely used to activate Hedgehog signalling via Patched1 deletion in specific cell types. The conditional mouse lines were crossed with a Math1-Cre line to delete the two genes in granule neuron progenitors from embryonic day 10.5. While deletion of only Patched1 as well as Patched1 together with RBP-J leads to formation of medulloblastoma concomitant with disorganisation of cell layers, loss of RBP-J from granule neuron progenitors has no obvious effect on overall cerebellar morphology or differentiation and maturation of the different cerebellar cell types. Conclusions Our results suggest that even though Notch signalling has been shown to play important roles in cerebellar development, signalling via RBP-J is surprisingly not required in granule neuron progenitors. Furthermore, RBP-J inactivation in these cells does not influence the formation of medulloblastoma initiated by Hedgehog pathway activation. This may suggest a requirement of Notch in cerebellar development at a different developmental stage or in a different cell type than examined here - for example, in the neural stem cells of the ventricular zone. In addition, it remains a possibility that, in granule neuron progenitors, Notch may signal via an alternative pathway without the requirement for RBP-J.
Collapse
Affiliation(s)
- Elaine Julian
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
| | | | | |
Collapse
|
|
30
|
Brandt MD, Maass A, Kempermann G, Storch A. Physical exercise increases Notch activity, proliferation and cell cycle exit of type-3 progenitor cells in adult hippocampal neurogenesis. Eur J Neurosci 2010; 32:1256-64. [PMID: 20950279 DOI: 10.1111/j.1460-9568.2010.07410.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
In adult hippocampal neurogenesis of mice, the proliferation of precursor cells can be stimulated by voluntary exercise (wheel-running). Physical activity has an additional effect on late progenitor cells (type-3) by promoting cell survival and further maturation. Notch1 is a key regulator of various steps in neuronal development, including the inhibition of cell cycle exit and neuronal differentiation of neural stem cells, as well as promoting the survival and dendritic branching of newborn neurons. We here report that physical activity increased the proportion and absolute number of doublecortin(+) (DCX) type-2b and type-3 progenitor cells that showed an activated Notch1 pathway. In contrast, the fraction of dividing cells with nuclear Notch intracellular domain expression indicating an activated Notch pathway was not affected by physical exercise. We used double labeling with two halogenated thymidine analogs, iododeoxyuridine and chlorodeoxyuridine, to distinguish between cell cycle exit and continued division at the progenitor cell level. After 7 days of physical exercise, the proliferative activity of precursor cells was increased, whereas the proportion of type-2b/3 cells re-entering S-phase was reduced. Consistent with this observation, the proportion of DCX(+) cells that expressed the marker of postmitotic immature granule cells (calretinin) was enhanced. Running promotes both the proliferation and cell cycle exit of DCX(+) type-3 precursors, possibly by preferentially stimulating a last neurogenic cell division. These pro-proliferative effects are independent of Notch1, whereas the running-induced survival and cell cycle exit of type-3 progenitor cells might by mediated by Notch1 activity.
Collapse
Affiliation(s)
- Moritz D Brandt
- Department of Neurology, Dresden University of Technology, Dresden, Germany
| | | | | | | |
Collapse
|
|
31
|
Notch signaling influences neuroprotective and proliferative properties of mature Müller glia. J Neurosci 2010; 30:3101-12. [PMID: 20181607 DOI: 10.1523/jneurosci.4919-09.2010] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Notch signaling is known to play important roles during retinal development. Recently, Notch signaling has been shown to be active in proliferating Müller glia in acutely damaged chick retina (Hayes et al., 2007). However, the roles of Notch in mature, undamaged retina remain unknown. Thus, the purpose of this study was to determine the role of the Notch-signaling pathway in the postnatal retina. Here we show that components of the Notch-signaling pathway are expressed in most Müller glia at low levels in undamaged retina. The expression of Notch-related genes varies during early postnatal development and across regions, with higher expression in peripheral versus central retina. Blockade of Notch activity with a small molecule inhibitor before damage was protective to retinal interneurons (amacrine and bipolar cells) and projection neurons (ganglion cells). In the absence of damage, Notch is upregulated in retinas treated with insulin and FGF2; the combination of these factors is known to stimulate the proliferation and dedifferentiation of Müller glia (Fischer et al., 2002b). Inhibition of Notch signaling during FGF2 treatment reduces levels of the downstream effectors of the MAPK-signaling pathway-p38 MAPK and pCREB in Müller glia. Further, inhibition of Notch activity potently inhibits FGF2-induced proliferation of Müller glia. Together, our data indicate that Notch signaling is downstream of, and is required for, FGF2/MAPK signaling to drive the proliferation of Müller glia. In addition, our data suggest that low levels of Notch signaling in Müller glia diminish the neuroprotective activities of these glial cells.
Collapse
|
|
32
|
Kim S, Lehtinen MK, Sessa A, Zappaterra MW, Cho SH, Gonzalez D, Boggan B, Austin CA, Wijnholds J, Gambello MJ, Malicki J, LaMantia AS, Broccoli V, Walsh CA. The apical complex couples cell fate and cell survival to cerebral cortical development. Neuron 2010; 66:69-84. [PMID: 20399730 DOI: 10.1016/j.neuron.2010.03.019] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2010] [Indexed: 01/05/2023]
Abstract
Cortical development depends upon tightly controlled cell fate and cell survival decisions that generate a functional neuronal population, but the coordination of these two processes is poorly understood. Here we show that conditional removal of a key apical complex protein, Pals1, causes premature withdrawal from the cell cycle, inducing excessive generation of early-born postmitotic neurons followed by surprisingly massive and rapid cell death, leading to the abrogation of virtually the entire cortical structure. Pals1 loss shows exquisite dosage sensitivity, so that heterozygote mutants show an intermediate phenotype on cell fate and cell death. Loss of Pals1 blocks essential cell survival signals, including the mammalian target of rapamycin (mTOR) pathway, while mTORC1 activation partially rescues Pals1 deficiency. These data highlight unexpected roles of the apical complex protein Pals1 in cell survival through interactions with mTOR signaling.
Collapse
Affiliation(s)
- Seonhee Kim
- Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Annenkov A. The insulin-like growth factor (IGF) receptor type 1 (IGF1R) as an essential component of the signalling network regulating neurogenesis. Mol Neurobiol 2009; 40:195-215. [PMID: 19714501 DOI: 10.1007/s12035-009-8081-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2009] [Accepted: 08/14/2009] [Indexed: 02/07/2023]
Abstract
The insulin-like growth factor receptor type 1 (IGF1R) signalling pathway is activated in the mammalian nervous system from early developmental stages. Its major effect on developing neural cells is to promote their growth and survival. This pathway can integrate its action with signalling pathways of growth and morphogenetic factors that induce cell fate specification and selective expansion of specified neural cell subsets. This suggests that during developmental and adult neurogenesis cellular responses to many signalling factors, including ligands of Notch, sonic hedgehog, fibroblast growth factor family members, ligands of the epidermal growth factor receptor, bone morphogenetic proteins and Wingless and Int-1, may be modified by co-activation of the IGF1R. Modulation of cell migration is another possible role that IGF1R activation may play in neurogenesis. Here, I briefly overview neurogenesis and discuss a role for IGF1R-mediated signalling in the developing and mature nervous system with emphasis on crosstalk between the signalling pathways of the IGF1R and other factors regulating neural cell development and migration. Studies on neural as well as on non-neural cells are highlighted because it may be interesting to test in neurogenic paradigms some of the models based on the information obtained in studies on non-neural cell types.
Collapse
Affiliation(s)
- Alexander Annenkov
- William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, UK.
| |
Collapse
|
|
34
|
Abstract
Notch is an integral membrane protein that functions as receptor for ligands such as jagged and delta that are associated with the surface of neighboring cells. Upon ligand binding, notch is proteolytically cleaved within its transmembrane domain by presenilin-1 (the enzymatic component of the gamma-secretase complex) resulting in the release of a notch intracellular domain which translocates to the nucleus where it regulates gene expression. Notch signaling plays multiple roles in the development of the CNS including regulating neural stem cell (NSC) proliferation, survival, self-renewal and differentiation. Notch is also present in post-mitotic neurons in the adult CNS wherein its activation influences structural and functional plasticity including processes involved in learning and memory. Recent findings suggest that notch signaling in neurons, glia, and NSCs may be involved in pathological changes that occur in disorders such as stroke, Alzheimer's disease and CNS tumors. Studies of animal models suggest the potential of agents that target notch signaling as therapeutic interventions for several different CNS disorders.
Collapse
Affiliation(s)
- Justin D Lathia
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA
| | | | | |
Collapse
|
|
35
|
Sui Y, Zhang Z, Guo Y, Sun Y, Zhang X, Xie C, Li Y, Xi G. The Function of Notch1 Signaling Was Increased in Parallel with Neurogenesis in Rat Hippocampus after Chronic Fluoxetine Administration. Biol Pharm Bull 2009; 32:1776-82. [DOI: 10.1248/bpb.32.1776] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Yuxiu Sui
- School of Clinical Medicine, Southeast University
- The Department of Psychiatry, Affiliated Nanjing Brain Hospital of Nanjing Medical University
| | - Zhijun Zhang
- School of Clinical Medicine, Southeast University
- The Department of Neurology, Affiliated ZhongDa Hospital of Southeast University
| | - Yijing Guo
- School of Clinical Medicine, Southeast University
- The Department of Neurology, Affiliated ZhongDa Hospital of Southeast University
| | - Yi Sun
- School of Clinical Medicine, Southeast University
| | | | - Chunming Xie
- School of Clinical Medicine, Southeast University
| | - Yuan Li
- The Department of Psychiatry, Affiliated Nanjing Brain Hospital of Nanjing Medical University
| | - Guangjun Xi
- School of Clinical Medicine, Southeast University
| |
Collapse
|
|
36
|
Wen S, Li H, Liu J. Epigenetic background of neuronal fate determination. Prog Neurobiol 2008; 87:98-117. [PMID: 19007844 DOI: 10.1016/j.pneurobio.2008.10.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2008] [Revised: 09/03/2008] [Accepted: 10/15/2008] [Indexed: 01/07/2023]
Abstract
The development of the central nervous system (CNS) starts from neural stem cells (NSCs). During this process, NSCs are specified in space- and time-related fashions, becoming spatially heterogeneous and generating a progressively restricted repertoire of cell types: neurons, astrocytes and oligodendrocytes. The processes of neurodevelopment are determined reciprocally by intrinsic and external factors which interface to program and re-program the profiling of fate-determination gene expression. Multiple signaling pathways act in a dynamic web mode to determine the fate of NSCs through modulating the activity of a distinct set of transcription factors which in turn trigger the transcription of neural fate-determination genes. Accumulating evidence reveals that during CNS development, multiple epigenetic factors regulate the activities of extracellular signaling and corresponding transcription factors in a coordinative manner, leading to the formation of a system with sophisticated structure and magic functions. This review aims to introduce recent advances in the epigenetic background of neural cell fate determination.
Collapse
Affiliation(s)
- Shu Wen
- Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, 116044 Dalian, Liaoning, PR China
| | | | | |
Collapse
|
|
37
|
Alpha-synuclein alters Notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice. J Neurosci 2008; 28:4250-60. [PMID: 18417705 DOI: 10.1523/jneurosci.0066-08.2008] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Altered expression and mutations in alpha-synuclein (alpha-syn) have been linked to Parkinson's disease (PD) and related disorders. The neurological alterations in PD patients have been associated with degeneration of dopaminergic cells and other neuronal populations. Moreover, recent studies in murine models have shown that alterations in neurogenesis might also contribute to the neurodegenerative phenotype. However, the mechanisms involved and the effects of alpha-syn expression on neurogenesis are not yet clear. To this end, murine embryonic stem (mES) cells were infected with lentiviral (LV) vectors expressing wild-type (WT) and mutant alpha-syn. Compared with mES cells infected with LV-green fluorescent protein (GFP), cells expressing WT and mutant alpha-syn showed reduced proliferation as indicated by lower 5-bromo-2'-deoxyuridine uptake, increased apoptosis, and reduced expression of neuronal markers such as neuron specific enolase and beta-III tubulin. The alterations in neurogenesis in alpha-syn-expressing mES cells were accompanied by a reduction in Notch-1 and Hairy and enhancer of split-5 (Hes-5) mRNA and protein levels. Moreover, levels of total Notch-1 and Notch intracellular domain (NICD) were lower in mES cells expressing WT and mutant alpha-syn compared with GFP controls. The reduced survival of alpha-syn-expressing mES cells was reverted by overexpressing constitutively active NICD. Similarly, in alpha-syn transgenic mice, the alterations in neurogenesis in the hippocampal subgranular zone were accompanied by decreased Notch-1, NICD, and Hes-5 expression. Together, these results suggest that accumulation of alpha-syn might impair survival of NPCs by interfering with the Notch signaling pathway. Similar mechanisms could be at play in PD and Lewy body disease.
Collapse
|
|
38
|
Pinto L, Mader MT, Irmler M, Gentilini M, Santoni F, Drechsel D, Blum R, Stahl R, Bulfone A, Malatesta P, Beckers J, Götz M. Prospective isolation of functionally distinct radial glial subtypes--lineage and transcriptome analysis. Mol Cell Neurosci 2008; 38:15-42. [PMID: 18372191 DOI: 10.1016/j.mcn.2008.01.012] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2007] [Accepted: 01/07/2008] [Indexed: 12/18/2022] Open
Abstract
Since the discovery of radial glia as the source of neurons, their heterogeneity in regard to neurogenesis has been described by clonal and time-lapse analysis in vitro. However, the molecular determinants specifying neurogenic radial glia differently from radial glia that mostly self-renew remain ill-defined. Here, we isolated two radial glial subsets that co-exist at mid-neurogenesis in the developing cerebral cortex and their immediate progeny. While one subset generates neurons directly, the other is largely non-neurogenic but also gives rise to Tbr2-positive basal precursors, thereby contributing indirectly to neurogenesis. Isolation of these distinct radial glia subtypes allowed determining interesting differences in their transcriptome. These transcriptomes were also strikingly different from the transcriptome of radial glia isolated at the end of neurogenesis. This analysis therefore identifies, for the first time, the lineage origin of basal progenitors and the molecular differences of this lineage in comparison to directly neurogenic and gliogenic radial glia.
Collapse
Affiliation(s)
- Luisa Pinto
- Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Institute of Stem Cell Research, Ingolstädter Landstr. 1, 85764 Neuherberg/Munich, Germany
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Abstract
More than half of the initially-formed neurons are deleted in certain brain regions during normal development. This process, whereby cells are discretely removed without interfering with the further development of remaining cells, is called programmed cell death (PCD). The term apoptosis is used to describe certain morphological manifestations of PCD. Many of the effectors of this developmental cell death program are highly expressed in the developing brain, making it more susceptible to accidental activation of the death machinery, e.g. following hypoxia-ischemia or irradiation. Recent evidence suggests, however, that activation and regulation of cell death mechanisms under pathological conditions do not exactly mirror physiological, developmentally regulated PCD. It may be argued that the conditions after e.g. ischemia are not even compatible with the execution of PCD as we know it. Under pathological conditions cells are exposed to various stressors, including energy failure, oxidative stress and unbalanced ion fluxes. This results in parallel triggering and potential overshooting of several different cell death pathways, which then interact with one another and result in complex patterns of biochemical manifestations and cellular morphological features. These types of cell death are here called "pathological apoptosis," where classical hallmarks of PCD, like pyknosis, nuclear condensation and caspase-3 activation, are combined with non-PCD features of cell death. Here we review our current knowledge of the mechanisms involved, with special focus on the potential for therapeutic intervention tailored to the needs of the developing brain.
Collapse
Affiliation(s)
- Klas Blomgren
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Göteborg University, SE 405 30 Göteborg, Sweden.
| | | | | |
Collapse
|
|
40
|
Chen J, Zacharek A, Li A, Cui X, Roberts C, Lu M, Chopp M. Atorvastatin promotes presenilin-1 expression and Notch1 activity and increases neural progenitor cell proliferation after stroke. Stroke 2007; 39:220-6. [PMID: 18063826 DOI: 10.1161/strokeaha.107.490946] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND PURPOSE Presenilin1 (PS1) regulates Notch1 signaling activity, which liberates Notch intracellular domain (NICD). Notch activation promotes neural progenitor cell (NPC) self-renewal in the developing brain. In this study, we tested whether atorvastatin-induced NPC proliferation after stroke is mediated by PS1 and Notch1 activation. METHODS PS1 and NICD expressions were measured in retired breeder rats subjected to middle cerebral artery occlusion that were left untreated or treated with atorvastatin. To investigate the mechanisms of atorvastatin-induced NPC self-renewal, subventricular zone (SVZ) neurosphere culture and knockdown of Notch1 gene expression by short interfering RNA were used. SVZ neurosphere formation, cell proliferation, real-time polymerase chain reaction, and Western blotting were performed. RESULTS Atorvastatin significantly increased the numbers of newly generated neuroblasts and promoted PS1 and NICD expression in the ipsilateral and homologous contralateral SVZ compared with saline-treated control rats. Increased SVZ neurosphere formation and cell proliferation were found in cultured neurospheres derived from normal rat and poststroke rat SVZs treated in vitro with atorvastatin compared with untreated neurospheres (P<0.05). Atorvastatin significantly increased PS1 and hairy and enhancer of split1 (Hes1) gene expression in cultured SVZ neurospheres. Inhibition of PS1 significantly decreased NICD expression. Short interfering RNA knockdown of Notch1 expression, decreased NPC proliferation, and NICD and hairy and enhancer of split1 expression in cultured neurosphere cells. CONCLUSIONS These data indicate that atorvastatin increases the NPC pool in older rats and that it also upregulates PS1 expression and Notch1 signaling activity, which in turn, facilitate an increase in SVZ NPC proliferation.
Collapse
Affiliation(s)
- Jieli Chen
- Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
| | | | | | | | | | | | | |
Collapse
|
|
41
|
Rodriguez S, Sickles HM, Deleonardis C, Alcaraz A, Gridley T, Lin DM. Notch2 is required for maintaining sustentacular cell function in the adult mouse main olfactory epithelium. Dev Biol 2007; 314:40-58. [PMID: 18155189 DOI: 10.1016/j.ydbio.2007.10.056] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2007] [Revised: 10/25/2007] [Accepted: 10/26/2007] [Indexed: 10/22/2022]
Abstract
Notch receptors are expressed in neurons and glia in the adult nervous system, but why this expression persists is not well-understood. Here we examine the role of the Notch pathway in the postnatal mouse main olfactory system, and show evidence consistent with a model where Notch2 is required for maintaining sustentacular cell function. In the absence of Notch2, the laminar nature of these glial-like cells is disrupted. Hes1, Hey1, and Six1, which are downstream effectors of the Notch pathway, are down-regulated, and cytochrome P450 and Glutathione S-transferase (GST) expression by sustentacular cells is reduced. Functional levels of GST activity are also reduced. These disruptions are associated with increased olfactory sensory neuron degeneration. Surprisingly, expression of Notch3 is also down-regulated. This suggests the existence of a feedback loop where expression of Notch3 is initially independent of Notch2, but requires Notch2 for maintained expression. While the Notch pathway has previously been shown to be important for promoting gliogenesis during development, this is the first demonstration that the persistent expression of Notch receptors is required for maintaining glial function in adult.
Collapse
Affiliation(s)
- Steve Rodriguez
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | | | | | | | | | | |
Collapse
|
|
42
|
Gray F, Polivka M, Viswanathan A, Baudrimont M, Bousser MG, Chabriat H. Apoptosis in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol 2007; 66:597-607. [PMID: 17620985 DOI: 10.1097/nen.0b013e318093e574] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
To test the hypothesis that an apoptotic process plays a role in the pathogenesis of cerebral lesions in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we examined samples from frontal, temporal, insular, and occipital regions, basal ganglia, and cerebellum from 4 patients with CADASIL, 2 with Binswanger disease, and 3 controls. Apoptotic cells were identified using in situ end labeling and activated caspase 3 immunostaining. Immunolabeling for Notch3, the beta-amyloid protein precursor, and phosphorylated neurofilament protein was performed on successive sections. Apoptosis of vascular cells was markedly increased in status cribrosus in CADASIL, both in basal ganglia and subcortical white matter, suggesting that concomitantly with Notch3 deposition it may play a causative role in the dilatation of Virchow-Robin spaces. Neuronal apoptosis was found in CADASIL, mostly in cortical layers 3 and 5. Its severity correlated semiquantitatively with the extent of ischemic lesions and axonal damage in the underlying white matter. It was more severe in demented patients. Only occasional apoptotic neurons were found in the Binswanger cases and none in the controls. This supports the view that neuronal apoptosis may contribute to cortical atrophy and cognitive impairment in patients with CADASIL and that it may, at least partly, result from axonal damage in the underlying white matter.
Collapse
Affiliation(s)
- Francoise Gray
- Department of Pathology, APHP Hôpital Lariboisière, Université Paris VII, 2 rue Ambroise Paré, 75475 Paris, France.
| | | | | | | | | | | |
Collapse
|
|
43
|
Nagao M, Sugimori M, Nakafuku M. Cross talk between notch and growth factor/cytokine signaling pathways in neural stem cells. Mol Cell Biol 2007; 27:3982-94. [PMID: 17371842 PMCID: PMC1900030 DOI: 10.1128/mcb.00170-07] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Precise control of proliferation and differentiation of multipotent neural stem cells (NSCs) is crucial for proper development of the nervous system. Although signaling through the cell surface receptor Notch has been implicated in many aspects of neural development, its role in NSCs remains elusive. Here we examined how the Notch pathway cross talks with signaling for growth factors and cytokines in controlling the self-renewal and differentiation of NSCs. Both Notch and growth factors were required for active proliferation of NSCs, but each of these signals was sufficient and independent of the other to inhibit differentiation of neurons and glia. Moreover, Notch signals could support the clonal self-renewing growth of NSCs in the absence of growth factors. This growth factor-independent action of Notch involved the regulation of the cell cycle and cell-cell interactions. During differentiation of NSCs, Notch signals promoted the generation of astrocytes in collaboration with ciliary neurotrophic factor and growth factors. Their cooperative actions were likely through synergistic phosphorylation of signal transducer and activator of transcription 3 on tyrosine at position 705 and serine at position 727. Our data suggest that distinct intracellular signaling pathways operate downstream of Notch for the self-renewal of NSCs and stimulation of astrogenesis.
Collapse
Affiliation(s)
- Motoshi Nagao
- Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA
| | | | | |
Collapse
|
|
44
|
Nelson BR, Hartman BH, Georgi SA, Lan MS, Reh TA. Transient inactivation of Notch signaling synchronizes differentiation of neural progenitor cells. Dev Biol 2007; 304:479-98. [PMID: 17280659 PMCID: PMC1979095 DOI: 10.1016/j.ydbio.2007.01.001] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2006] [Revised: 12/23/2006] [Accepted: 01/02/2007] [Indexed: 11/19/2022]
Abstract
In the developing nervous system, the balance between proliferation and differentiation is critical to generate the appropriate numbers and types of neurons and glia. Notch signaling maintains the progenitor pool throughout this process. While many components of the Notch pathway have been identified, the downstream molecular events leading to neural differentiation are not well understood. We have taken advantage of a small molecule inhibitor, DAPT, to block Notch activity in retinal progenitor cells, and analyzed the resulting molecular and cellular changes over time. DAPT treatment causes a massive, coordinated differentiation of progenitors that produces cell types appropriate for their developmental stage. Transient exposure of retina to DAPT for specific time periods allowed us to define the period of Notch inactivation that is required for a permanent commitment to differentiate. Inactivation of Notch signaling revealed a cascade of proneural bHLH transcription factor gene expression that correlates with stages in progenitor cell differentiation. Microarray/QPCR analysis confirms the changes in Notch signaling components, and reveals new molecular targets for investigating neuronal differentiation. Thus, transient inactivation of Notch signaling synchronizes progenitor cell differentiation, and allows for a systematic analysis of key steps in this process.
Collapse
Affiliation(s)
- Branden R. Nelson
- Department of Biological Structure, University of Washington, Seattle, WA 98195
| | - Byron H. Hartman
- Department of Biological Structure, University of Washington, Seattle, WA 98195
| | - Sean A. Georgi
- Neurobiology and Behavior Program, University of Washington, Seattle, WA 98195
| | - Michael S. Lan
- The Research Institute for Children, Children's Hospital, New Orleans, LA 70118
| | - Thomas A. Reh
- Department of Biological Structure, University of Washington, Seattle, WA 98195
- Neurobiology and Behavior Program, University of Washington, Seattle, WA 98195
- Author for correspondence: Dr. T.A. Reh, Department of Biological Structure, Box 357420, University of Washington, Seattle, WA 98195, , phone 206-543-8043, fax 206-543-1524
| |
Collapse
|
|
45
|
Deneen B, Ho R, Lukaszewicz A, Hochstim CJ, Gronostajski RM, Anderson DJ. The Transcription Factor NFIA Controls the Onset of Gliogenesis in the Developing Spinal Cord. Neuron 2006; 52:953-68. [PMID: 17178400 DOI: 10.1016/j.neuron.2006.11.019] [Citation(s) in RCA: 381] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2006] [Revised: 09/12/2006] [Accepted: 11/16/2006] [Indexed: 11/25/2022]
Abstract
The mechanisms controlling the transition from neurogenesis to gliogenesis in the vertebrate CNS are incompletely understood. We identified a family of transcription factors, called NFI genes, which are induced throughout the spinal cord ventricular zone (VZ) concomitantly with the induction of GLAST, an early marker of gliogenesis. NFIA is both necessary and sufficient for GLAST induction in the VZ. Unexpectedly, NFIA is also essential for the continued inhibition of neurogenesis in VZ progenitors. This function is mediated by the requirement of NFIA for the expression of HES5, a Notch effector. However, Notch effectors are unable to promote glial-fate specification in the absence of NFIA. Thus, NFIA links the abrogation of neurogenesis to a generic program of gliogenesis, in both astrocyte and oligodendrocyte VZ progenitors. At later stages, NFIA promotes migration and differentiation of astrocyte precursors, a function that is antagonized in oligodendrocyte precursors by Olig2.
Collapse
Affiliation(s)
- Benjamin Deneen
- Division of Biology 216-76, California Institute of Technology, 1201 East California Boulevard, Pasadena, California 91125, USA
| | | | | | | | | | | |
Collapse
|
|
46
|
Givogri MI, de Planell M, Galbiati F, Superchi D, Gritti A, Vescovi A, de Vellis J, Bongarzone ER. Notch signaling in astrocytes and neuroblasts of the adult subventricular zone in health and after cortical injury. Dev Neurosci 2006; 28:81-91. [PMID: 16508306 DOI: 10.1159/000090755] [Citation(s) in RCA: 113] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2005] [Accepted: 09/19/2005] [Indexed: 11/19/2022] Open
Abstract
The postnatal subventricular zone (SVZ) is a niche for continuous neurogenesis in the adult brain and likely plays a fundamental role in self-repair responses in neurodegenerative conditions. Maintenance of the pool of neural stem cells within this area depends on cell-cell communication such as that provided by the Notch signaling pathway. Notch1 receptor mRNA has been found distributed in different areas of the postnatal brain including the SVZ. Although the identity of Notch1-expressing cells has been established in the majority of these areas, it is still unclear what cell types within the SVZ are expressing components of this pathway. Here we demonstrate that most of expression of Notch1 in the adult SVZ occurs in polysialylated neural cell adhesion molecule (PSA-NCAM)-positive neural precursors and in glial fibrillary acidic protein-positive SVZ astrocytes. Notch1 was also found in PSA-NCAM-positive neuroblasts located within the rostral migratory stream (RMS) but much less in those that have reached the olfactory bulb. We show that two of the naturally occurring Notch1 activators, Jagged1 and Delta1, are also expressed in the SVZ and within the RMS in the adult mouse brain. Finally, using a model of cortical stab wound, we show that the astrogliogenic response of the SVZ to injury is accompanied by activation of the Notch pathway.
Collapse
Affiliation(s)
- Maria I Givogri
- Laboratory for Gene Therapy of Neurodegenerative Disorders, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
| | | | | | | | | | | | | | | |
Collapse
|