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Zhou Y, Li H, Liu X, Chi X, Gu Z, Cui B, Bergquist J, Wang B, Tian G, Yang C, Xu F, Mi J. The Combination of Quantitative Proteomics and Systems Genetics Analysis Reveals that PTN Is Associated with Sleep-Loss-Induced Cognitive Impairment. J Proteome Res 2023; 22:2936-2949. [PMID: 37611228 DOI: 10.1021/acs.jproteome.3c00269] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Sleep loss is associated with cognitive dysfunction. However, the detailed mechanisms remain unclear. In this study, we established a para-chlorophenylalanine (PCPA)-induced insomniac mouse model with impaired cognitive function. Mass-spectrometry-based proteomics showed that the expression of 164 proteins was significantly altered in the hippocampus of the PCPA mice. To identify critical regulators among the potential markers, a transcriptome-wide association screening was performed in the BXD mice panel. Among the candidates, the expression of pleiotrophin (Ptn) was significantly associated with cognitive functions, indicating that Ptn-mediates sleep-loss-induced cognitive impairment. Gene co-expression analysis further revealed the potential mechanism by which Ptn mediates insomnia-induced cognitive impairment via the MAPK signaling pathway; that is, the decreased secretion of Ptn induced by insomnia leads to reduced binding to Ptprz1 on the postsynaptic membrane with the activation of the MAPK pathway via Fos and Nr4a1, further leading to the apoptosis of neurons. In addition, Ptn is genetically trans-regulated in the mouse hippocampus and implicated in neurodegenerative diseases in human genome-wide association studies. Our study provides a novel biomarker for insomnia-induced cognitive impairment and a new strategy for seeking neurological biomarkers by the integration of proteomics and systems genetics.
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Affiliation(s)
- Yutong Zhou
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Hui Li
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Xiaoya Liu
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Xiaodong Chi
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Zhaoxi Gu
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Binsen Cui
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Jonas Bergquist
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
- Department of Chemistry-BMC, Analytical Chemistry and Neurochemistry, Uppsala University, Uppsala 75124, Sweden
| | - Binsheng Wang
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Geng Tian
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Chunhua Yang
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Fuyi Xu
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
| | - Jia Mi
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, Shandong 264003, China
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Brown TE, Sorg BA. Net gain and loss: influence of natural rewards and drugs of abuse on perineuronal nets. Neuropsychopharmacology 2023; 48:3-20. [PMID: 35568740 PMCID: PMC9700711 DOI: 10.1038/s41386-022-01337-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 12/26/2022]
Abstract
Overindulgence, excessive consumption, and a pattern of compulsive use of natural rewards, such as certain foods or drugs of abuse, may result in the development of obesity or substance use disorder, respectively. Natural rewards and drugs of abuse can trigger similar changes in the neurobiological substrates that drive food- and drug-seeking behaviors. This review examines the impact natural rewards and drugs of abuse have on perineuronal nets (PNNs). PNNs are specialized extracellular matrix structures that ensheathe certain neurons during development over the critical period to provide synaptic stabilization and a protective microenvironment for the cells they surround. This review also analyzes how natural rewards and drugs of abuse impact the density and maturation of PNNs within reward-associated circuitry of the brain, which may contribute to maladaptive food- and drug-seeking behaviors. Finally, we evaluate the relatively few studies that have degraded PNNs to perturb reward-seeking behaviors. Taken together, this review sheds light on the complex way PNNs are regulated by natural rewards and drugs and highlights a need for future studies to delineate the molecular mechanisms that underlie the modification and maintenance of PNNs following exposure to rewarding stimuli.
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Affiliation(s)
- Travis E Brown
- Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, 99164, USA.
| | - Barbara A Sorg
- R.S. Dow Neurobiology, Legacy Research Institute, Portland, OR, 97232, USA
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Astorkia M, Lachman HM, Zheng D. Characterization of cell-cell communication in autistic brains with single-cell transcriptomes. J Neurodev Disord 2022; 14:29. [PMID: 35501678 PMCID: PMC9059394 DOI: 10.1186/s11689-022-09441-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 04/18/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Autism spectrum disorder is a neurodevelopmental disorder, affecting 1-2% of children. Studies have revealed genetic and cellular abnormalities in the brains of affected individuals, leading to both regional and distal cell communication deficits. METHODS Recent application of single-cell technologies, especially single-cell transcriptomics, has significantly expanded our understanding of brain cell heterogeneity and further demonstrated that multiple cell types and brain layers or regions are perturbed in autism. The underlying high-dimensional single-cell data provides opportunities for multilevel computational analysis that collectively can better deconvolute the molecular and cellular events altered in autism. Here, we apply advanced computation and pattern recognition approaches on single-cell RNA-seq data to infer and compare inter-cell-type signaling communications in autism brains and controls. RESULTS Our results indicate that at a global level, there are cell-cell communication differences in autism in comparison with controls, largely involving neurons as both signaling senders and receivers, but glia also contribute to the communication disruption. Although the magnitude of changes is moderate, we find that excitatory and inhibitor neurons are involved in multiple intercellular signaling that exhibits increased strengths in autism, such as NRXN and CNTN signaling. Not all genes in the intercellular signaling pathways show differential expression, but genes in the affected pathways are enriched for axon guidance, synapse organization, neuron migration, and other critical cellular functions. Furthermore, those genes are highly connected to and enriched for genes previously associated with autism risks. CONCLUSIONS Overall, our proof-of-principle computational study using single-cell data uncovers key intercellular signaling pathways that are potentially disrupted in the autism brains, suggesting that more studies examining cross-cell type effects can be valuable for understanding autism pathogenesis.
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Affiliation(s)
- Maider Astorkia
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Herbert M Lachman
- Department of Psychiatry, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
- Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Deyou Zheng
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
- Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
- Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
- Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
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Oentaryo MJ, Tse ACK, Lee CW. Neuronal MT1-MMP mediates ECM clearance and Lrp4 cleavage for agrin deposition and signaling in presynaptic development. J Cell Sci 2020; 133:jcs246710. [PMID: 32591486 DOI: 10.1242/jcs.246710] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 06/16/2020] [Indexed: 08/31/2023] Open
Abstract
Agrin is a crucial factor that induces postsynaptic differentiation at neuromuscular junctions (NMJs), but how secreted agrin is locally deposited in the context of extracellular matrix (ECM) environment and its function in presynaptic differentiation remain largely unclear. Here, we report that the proteolytic activity of neuronal membrane-type 1 matrix metalloproteinase (MT1-MMP; also known as MMP14) facilitates agrin deposition and signaling during presynaptic development at NMJs. Firstly, agrin deposition along axons exhibits a time-dependent increase in cultured neurons that requires MMP-mediated focal ECM degradation. Next, local agrin stimulation induces the clustering of mitochondria and synaptic vesicles, two well-known presynaptic markers, and regulates vesicular trafficking and surface insertion of MT1-MMP. MMP inhibitor or MT1-MMP knockdown suppresses agrin-induced presynaptic differentiation, which can be rescued by treatment with the ectodomain of low-density lipoprotein receptor-related protein 4 (Lrp4). Finally, neuronal MT1-MMP knockdown inhibits agrin deposition and nerve-induced acetylcholine receptor clustering in nerve-muscle co-cultures and affects synaptic structures at Xenopus NMJs in vivo Collectively, our results demonstrate a previously unappreciated role of agrin, as well as dual functions of neuronal MT1-MMP proteolytic activity in orchestrating agrin deposition and signaling, in presynaptic development.
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Affiliation(s)
- Marilyn Janice Oentaryo
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Anna Chung-Kwan Tse
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Chi Wai Lee
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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Petrusel L, Rusu I, Leucuta DC, Seicean R, Suharoschi R, Zamfir P, Seicean A. Relationship between cachexia and perineural invasion in pancreatic adenocarcinoma. World J Gastrointest Oncol 2019; 11:1126-1140. [PMID: 31908718 PMCID: PMC6937437 DOI: 10.4251/wjgo.v11.i12.1126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 09/09/2019] [Accepted: 10/14/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cachexia is responsible for the low quality of life in pancreatic adenocarcinoma (PDAC). The rapid disease progression and patient deterioration seems related to perineural invasion, but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied. As perineural invasion is difficult to be highlighted, a biomarker such as the neurotrophic factor Midkine (MK) which promotes the neuronal differentiation and the cell migration could be helpful. Also, Activin (ACV) has been described as cachexia related to PDAC. However, their role for assessing and predicting the disease course in daily practice is not known. AIM To assess the relationship between perineural invasion and cachexia and their biomarkers, MK and ACV, respectively, and their prognostic value. METHODS This study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies. Patients with other causes of malnutrition were excluded. The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data. These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease. RESULTS The study comprised 114 patients with PDAC, 125 controls and a supplementary group of 14 benign pancreatic tissue samples. ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls (63% vs 32% for ACV, P < 0.001; 47% vs 16% for MK, P < 0.001), with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage (P = 0.006), the presence of metastasis (P = 0.04), perineural invasion (P = 0.03) and diabetes (P = 0.002), but with no influence on survival. No correlation between clinicopathological factors and ACV expression was noted. Cachexia, present in 19% of patients, was unrelated to ACV or MK level. Higher ACV expression was associated with a shorter survival (P = 0.008). CONCLUSION The MK was a biomarker of perineural invasion, associated with tumor stage and diabetes, but without prognostic value as ACV. Cachexia was unrelated to perineural invasion, ACV level or survival.
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Affiliation(s)
- Livia Petrusel
- Department of Gastroenterology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400162, Romania
| | - Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400162, Romania
| | - Daniel Corneliu Leucuta
- Medical Informatics and Biostatistics Department, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400012, Romania
| | - Radu Seicean
- First Surgery Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400006, Romania
| | - Ramona Suharoschi
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca 400372, Romania
| | - Paula Zamfir
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400162, Romania
| | - Andrada Seicean
- Department of Gastroenterology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400162, Romania
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Han KA, Um JW, Ko J. Intracellular protein complexes involved in synapse assembly in presynaptic neurons. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2018; 116:347-373. [PMID: 31036296 DOI: 10.1016/bs.apcsb.2018.11.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The presynaptic active zone, composed of evolutionarily conserved protein complexes, is a specialized area that serves to orchestrate precise and efficient neurotransmitter release by organizing various presynaptic proteins involved in mediating docking and priming of synaptic vesicles, recruiting voltage-gated calcium channels, and modulating presynaptic nerve terminals with aligned postsynaptic structures. Among membrane proteins localized to active zone, presynaptic neurexins and LAR-RPTPs (leukocyte common antigen-related receptor tyrosine phosphatase) have emerged as hubs that orchestrate both shared and distinct extracellular synaptic adhesion pathways. In this chapter, we discuss intracellular signaling cascades involved in recruiting various intracellular proteins at both excitatory and inhibitory synaptic sites. In particular, we highlight recent studies on key active zone proteins that physically and functionally link these cascades with neurexins and LAR-RPTPs in both vertebrate and invertebrate model systems. These studies allow us to build a general, universal view of how presynaptic active zones operate together with postsynaptic structures in neural circuits.
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Affiliation(s)
- Kyung Ah Han
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea
| | - Ji Won Um
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea
| | - Jaewon Ko
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea.
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Liu F, Huang J, Zhang L, Chen J, Zeng Y, Tang Y, Liu Z. Advances in Cerebral Organoid Systems and their Application in Disease Modeling. Neuroscience 2018; 399:28-38. [PMID: 30578974 DOI: 10.1016/j.neuroscience.2018.12.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/08/2018] [Accepted: 12/12/2018] [Indexed: 01/09/2023]
Abstract
Processes associated with human brain development and function are exceedingly complex, limiting our capacity to investigate disease status and potential treatment strategies in vitro. Recent advancements in human cerebral organoid systems-which replicate early stage neural tube formation, neuroepithelium differentiation, and whole-brain regional differentiation-have allowed researchers to generate more accurate models of brain development and disease. The generation of region-specific cerebral organoids also allows for the direct investigation of the etiology and pathological processes associated with inherited and acquired brain diseases, drug discovery, and drug toxicity. In this review, we provide an overview of various neural differentiation technologies, as well as a critical analysis of their strengths and limitations. We primarily focus on the generation of three-dimensional brain organoid systems and their application in infectious disease modeling, high-throughput compound screening, and neurodevelopmental disease modeling.
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Affiliation(s)
- Fangkun Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University (CSU), Changsha, China
| | - Jing Huang
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Mental Health Institute of the Second Xiangya Hospital, Central South University, Chinese National Clinical Research Center on Mental Disorders (xiangya), Chinese National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan 410011, China
| | - Liyang Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University (CSU), Changsha, China
| | - Jindong Chen
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Mental Health Institute of the Second Xiangya Hospital, Central South University, Chinese National Clinical Research Center on Mental Disorders (xiangya), Chinese National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan 410011, China
| | - Yu Zeng
- Department of Neurosurgery, Xiangya Hospital, Central South University (CSU), Changsha, China
| | - Yongjian Tang
- Department of Neurosurgery, Xiangya Hospital, Central South University (CSU), Changsha, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University (CSU), Changsha, China.
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Lizen B, Hutlet B, Bissen D, Sauvegarde D, Hermant M, Ahn MT, Gofflot F. HOXA5 localization in postnatal and adult mouse brain is suggestive of regulatory roles in postmitotic neurons. J Comp Neurol 2016; 525:1155-1175. [PMID: 27650319 DOI: 10.1002/cne.24123] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 09/08/2016] [Accepted: 09/15/2016] [Indexed: 01/13/2023]
Abstract
Hoxa5 is a member of the Hox gene family, which plays critical roles in successive steps of the central nervous system formation during embryonic and fetal development. Hoxa5 expression in the adult mouse brain has been reported, suggesting that this gene may be functionally required in the brain after birth. To provide further insight into the Hoxa5 expression pattern and potential functions in the brain, we have characterized its neuroanatomical profile from embryonic stages to adulthood. While most Hox mapping studies have been based solely on transcript analysis, we extended our analysis to HOXA5 protein localization in adulthood using specific antibodies. Our results show that Hoxa5 expression appears in the most caudal part of the hindbrain at fetal stages, where it is maintained until adulthood. In the medulla oblongata and pons, we detected Hoxa5 expression in many precerebellar neurons and in several nuclei implicated in the control of autonomic functions. In these territories, the HOXA5 protein is present solely in neurons, specifically in γ-aminobutyric acid (GABA)ergic, glutamatergic, and catecholaminergic neurons. Finally, we also detected Hoxa5 transcripts, but not the HOXA5 protein, in the thalamus and the cortex, from postnatal stages to adult stages, and in the cerebellum at adulthood. We provide evidence that some larger variants of Hoxa5 transcripts are present in these territories. Our mapping analysis allowed us to build hypotheses regarding HOXA5 functions in the nervous system after birth, such as a potential role in the establishment and refinement/plasticity of precerebellar circuits during postnatal and adult life. J. Comp. Neurol. 525:1155-1175, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Benoit Lizen
- Institute of Life Sciences, Catholic University of Louvain, 1348, Louvain-la-Neuve, Belgium
| | - Bertrand Hutlet
- Institute of Life Sciences, Catholic University of Louvain, 1348, Louvain-la-Neuve, Belgium
| | - Diane Bissen
- Institute of Life Sciences, Catholic University of Louvain, 1348, Louvain-la-Neuve, Belgium
| | - Deborah Sauvegarde
- Institute of Life Sciences, Catholic University of Louvain, 1348, Louvain-la-Neuve, Belgium
| | - Maryse Hermant
- Institute of Life Sciences, Catholic University of Louvain, 1348, Louvain-la-Neuve, Belgium
| | - Marie-Thérèse Ahn
- Institute of Life Sciences, Catholic University of Louvain, 1348, Louvain-la-Neuve, Belgium
| | - Françoise Gofflot
- Institute of Life Sciences, Catholic University of Louvain, 1348, Louvain-la-Neuve, Belgium
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González-Castillo C, Ortuño-Sahagún D, Guzmán-Brambila C, Márquez-Aguirre AL, Raisman-Vozari R, Pallás M, Rojas-Mayorquín AE. The absence of pleiotrophin modulates gene expression in the hippocampus in vivo and in cerebellar granule cells in vitro. Mol Cell Neurosci 2016; 75:113-21. [PMID: 27468976 DOI: 10.1016/j.mcn.2016.07.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 07/04/2016] [Accepted: 07/25/2016] [Indexed: 12/28/2022] Open
Abstract
Pleiotrophin (PTN) is a secreted growth factor recently proposed to act as a neuromodulatory peptide in the Central Nervous System. PTN appears to be involved in neurodegenerative diseases and neural disorders, and it has also been implicated in learning and memory. Specifically, PTN-deficient mice exhibit a lower threshold for LTP induction in the hippocampus, which is attenuated in mice overexpressing PTN. However, there is little information about the signaling systems recruited by PTN to modulate neural activity. To address this issue, the gene expression profile in hippocampus of mice lacking PTN was analyzed using microarrays of 22,000 genes. In addition, we corroborated the effect of the absence of PTN on the expression of these genes by silencing this growth factor in primary neuronal cultures in vitro. The microarray analysis identified 102 genes that are differentially expressed (z-score>3.0) in PTN null mice, and the expression of eight of those modified in the hippocampus of KO mice was also modified in vitro after silencing PTN in cultured neurons with siRNAs. The data obtained indicate that the absence of PTN affects AKT pathway response and modulates the expression of genes related with neuroprotection (Mgst3 and Estrogen receptor 1, Ers 1) and cell differentiation (Caspase 6, Nestin, and Odz4), both in vivo and in vitro.
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Affiliation(s)
- Celia González-Castillo
- Doctorado en Ciencias en Biología Molecular en Medicina (DCBMM), CUCS, Universidad de Guadalajara, Jalisco, Mexico
| | - Daniel Ortuño-Sahagún
- Instituto de Investigación en Ciencias Biomédicas (IICB), CUCS, Universidad de Guadalajara, Jalisco, Mexico.
| | - Carolina Guzmán-Brambila
- Tecnológico de Monterrey, División de Biotecnología y Salud, Escuela de Medicina, Campus Guadalajara, Jalisco, Mexico
| | - Ana Laura Márquez-Aguirre
- Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco A.C., 44270 Guadalajara, Jalisco, Mexico
| | - Rita Raisman-Vozari
- Sorbonne Université UPMC UM75 INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France
| | - Mercé Pallás
- Department of Pharmacology and Medical Chemistry, Faculty of Pharmacy, Institute of Neuroscience (INUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), University of Barcelona, Spain
| | - Argelia E Rojas-Mayorquín
- Departamento de Ciencias Ambientales, Instituto de Neurociencias, CUCBA, Universidad de Guadalajara, Jalisco, Mexico.
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González-Castillo C, Ortuño-Sahagún D, Guzmán-Brambila C, Pallàs M, Rojas-Mayorquín AE. Pleiotrophin as a central nervous system neuromodulator, evidences from the hippocampus. Front Cell Neurosci 2015; 8:443. [PMID: 25620911 PMCID: PMC4287103 DOI: 10.3389/fncel.2014.00443] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 12/10/2014] [Indexed: 02/04/2023] Open
Abstract
Pleiotrophin (PTN) is a secreted growth factor, and also a cytokine, associated with the extracellular matrix, which has recently starting to attract attention as a significant neuromodulator with multiple neuronal functions during development. PTN is expressed in several tissues, where its signals are generally related with cell proliferation, growth, and differentiation by acting through different receptors. In Central Nervous System (CNS), PTN exerts post-developmental neurotrophic and -protective effects, and additionally has been involved in neurodegenerative diseases and neural disorders. Studies in Drosophila shed light on some aspects of the different levels of regulatory control of PTN invertebrate homologs. Specifically in hippocampus, recent evidence from PTN Knock-out (KO) mice involves PTN functioning in learning and memory. In this paper, we summarize, discuss, and contrast the most recent advances and results that lead to proposing a PTN as a neuromodulatory molecule in the CNS, particularly in hippocampus.
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Affiliation(s)
- Celia González-Castillo
- Doctorwado en Ciencias en Biología Molecular en Medicina (DCBMM), CUCS, Universidad de Guadalajara Guadalajara, Jalisco, México
| | - Daniel Ortuño-Sahagún
- Instituto de Investigación en Ciencias Biomédicas (IICB), CUCS, Universidad de Guadalajara, Guadalajara Jalisco, México
| | - Carolina Guzmán-Brambila
- Tecnológico de Monterrey, División de Biotecnología y Salud, Escuela de Medicina, Campus Guadalajara Guadalajara, Jalisco, México
| | - Mercè Pallàs
- Department of Pharmacology and Medical Chemistry, Faculty of Pharmacy School of Pharmacy, Institute of Biomedicine (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), University of Barcelona Barcelona, Spain
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Proteoglycans of reactive rat cortical astrocyte cultures: abundance of N-unsubstituted glucosamine-enriched heparan sulfate. Matrix Biol 2014; 41:8-18. [PMID: 25483985 DOI: 10.1016/j.matbio.2014.11.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 11/15/2014] [Accepted: 11/16/2014] [Indexed: 11/22/2022]
Abstract
"Reactive" astrocytes and other glial cells in the injured CNS produce an altered extracellular matrix (ECM) that influences neuronal regeneration. We have profiled the glycosaminoglycan (GAG) component of proteoglycans (PGs) produced by reactive neonatal rat cortical astrocytes, and have quantified their neurite-outgrowth inhibitory activity. PGs extracted from cell layers and medium were fractionated on DEAE-Sephacel with a gradient of NaCl from 0.15 to 1.0 M. Monosaccharide analysis of the major peaks eluting at 0.6 M NaCl indicated an excess of GlcNH₂ to GalNH₂, suggesting an approximate HS/CS ratio of 6.2 in the cell layer and 4.2 in the medium. Chondroitinase ABC-generated disaccharide analysis of cell and medium PGs showed a >5-fold excess of chondroitin 4-sulfate over chondroitin 6-sulfate. Heparin lyase-generated disaccharides characteristic of the highly sulfated S-domain regions within HS were more abundant in cell layer than medium-derived PGs. Cell layer and medium HS disaccharides contained ~20% and ~40% N-unsubstituted glucosamine respectively, which is normally rare in HS isolated from most tissues. NGF-stimulated neurite outgrowth assays using NS-1 (PC12) neuronal cells on adsorbed substrata of PGs isolated from reactive astrocyte medium showed pronounced inhibition of neurite outgrowth, and aggregation of NS-1 cells. Cell layer PGs from DEAE-Sephacel pooled fractions having high charge density permitted greater NGF-stimulated outgrowth than PGs with lower charge density. Our results indicate the synthesis of both inhibitory and permissive PGs by activated astrocytes that may correlate with sulfation patterns and HS/CS ratios.
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12
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Behavioral and neuroanatomical abnormalities in pleiotrophin knockout mice. PLoS One 2014; 9:e100597. [PMID: 25000129 PMCID: PMC4085064 DOI: 10.1371/journal.pone.0100597] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 05/28/2014] [Indexed: 11/30/2022] Open
Abstract
Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.
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13
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Pamies D, Hartung T, Hogberg HT. Biological and medical applications of a brain-on-a-chip. Exp Biol Med (Maywood) 2014; 239:1096-1107. [PMID: 24912505 DOI: 10.1177/1535370214537738] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The desire to develop and evaluate drugs as potential countermeasures for biological and chemical threats requires test systems that can also substitute for the clinical trials normally crucial for drug development. Current animal models have limited predictivity for drug efficacy in humans as the large majority of drugs fails in clinical trials. We have limited understanding of the function of the central nervous system and the complexity of the brain, especially during development and neuronal plasticity. Simple in vitro systems do not represent physiology and function of the brain. Moreover, the difficulty of studying interactions between human genetics and environmental factors leads to lack of knowledge about the events that induce neurological diseases. Microphysiological systems (MPS) promise to generate more complex in vitro human models that better simulate the organ's biology and function. MPS combine different cell types in a specific three-dimensional (3D) configuration to simulate organs with a concrete function. The final aim of these MPS is to combine different "organoids" to generate a human-on-a-chip, an approach that would allow studies of complex physiological organ interactions. The recent discovery of induced pluripotent stem cells (iPSCs) gives a range of possibilities allowing cellular studies of individuals with different genetic backgrounds (e.g., human disease models). Application of iPSCs from different donors in MPS gives the opportunity to better understand mechanisms of the disease and can be a novel tool in drug development, toxicology, and medicine. In order to generate a brain-on-a-chip, we have established a 3D model from human iPSCs based on our experience with a 3D rat primary aggregating brain model. After four weeks of differentiation, human 3D aggregates stain positive for different neuronal markers and show higher gene expression of various neuronal differentiation markers compared to 2D cultures. Here we present the applications and challenges of this emerging technology.
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Affiliation(s)
- David Pamies
- Centers for Alternatives to Animal Testing (CAAT) at Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD 21205, USA; University of Konstanz, POB 600, Konstanz 78457, Germany
| | - Thomas Hartung
- Centers for Alternatives to Animal Testing (CAAT) at Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD 21205, USA; University of Konstanz, POB 600, Konstanz 78457, Germany
| | - Helena T Hogberg
- Centers for Alternatives to Animal Testing (CAAT) at Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD 21205, USA; University of Konstanz, POB 600, Konstanz 78457, Germany
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14
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Yao J, Li WY, Li SG, Feng XS, Gao SG. Midkine promotes perineural invasion in human pancreatic cancer. World J Gastroenterol 2014; 20:3018-3024. [PMID: 24659893 PMCID: PMC3960408 DOI: 10.3748/wjg.v20.i11.3018] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 10/24/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate midkine (MK) and syndecan-3 protein expression in pancreatic cancer by immunohistochemistry, and to analyze their correlation with clinicopathological features, perineural invasion, and prognosis.
METHODS: Pancreatic cancer tissues (including adequately sized tumor tissue samples and tissue samples taken from areas less than 2.0 cm around the tumor) were taken from 42 patients who were undergoing a partial duodenopancreatectomy. MK and syndecan-3 proteins were detected by immunohistochemistry using a standardized streptavidin-peroxidase method, and analyzed for their correlation with clinicopathological features, perineural invasion, and prognosis. Associations of neural invasion with aggressive characteristics of pancreatic cancer and the presence of perineural invasion were assessed by two independent observers blinded to the patient status.
RESULTS: MK and syndecan-3 were found in 26 (61.9%) and 24 (57.1%) specimens, respectively. MK and syndecan-3 expression was associated with perineural invasion (P = 0.018 and 0.031, respectively). High MK expression was closely associated with advanced tumor, node and metastasis stage (P = 0.008), lymph node metastasis (P = 0.042), and decreased postoperative survival at 3 years (51.0% vs 21.8%, P = 0.001). Syndecan-3 levels were correlated with tumor size (P = 0.028). Patients who were syndecan-3 negative had a higher cumulative survival rate than those who were positive, but the difference was not significant (44.0% vs 23.0%, P > 0.05).
CONCLUSION: MK and syndecan-3 are frequently expressed in pancreatic cancer and associated with perineural invasion. High expression of MK and syndecan-3 may contribute to the highly perineural invasion and poor prognosis of human pancreatic cancer.
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15
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Herradón G, Pérez-García C. Targeting midkine and pleiotrophin signalling pathways in addiction and neurodegenerative disorders: recent progress and perspectives. Br J Pharmacol 2014; 171:837-48. [PMID: 23889475 PMCID: PMC3925022 DOI: 10.1111/bph.12312] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 07/09/2013] [Accepted: 07/21/2013] [Indexed: 01/03/2023] Open
Abstract
UNLABELLED Midkine (MK) and pleiotrophin (PTN) are two neurotrophic factors that are highly up-regulated in different brain regions after the administration of various drugs of abuse and in degenerative areas of the brain. A deficiency in both MK and PTN has been suggested to be an important genetic factor, which confers vulnerability to the development of the neurodegenerative disorders associated with drugs of abuse in humans. In this review, evidence demonstrating that MK and PTN limit the rewarding effects of drugs of abuse and, potentially, prevent drug relapse is compiled. There is also convincing evidence that MK and PTN have neuroprotective effects against the neurotoxicity and development of neurodegenerative disorders induced by drugs of abuse. Exogenous administration of MK and/or PTN into the CNS by means of non-invasive methods is proposed as a novel therapeutic strategy for addictive and neurodegenerative diseases. Identification of new molecular targets downstream of the MK and PTN signalling pathways or pharmacological modulation of those already known may also provide a more traditional, but probably effective, therapeutic strategy for treating addictive and neurodegenerative disorders. LINKED ARTICLES This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.
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Affiliation(s)
- G Herradón
- Pharmacology lab Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San PabloBoadilla del Monte, Madrid, Spain
| | - C Pérez-García
- Pharmacology lab Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San PabloBoadilla del Monte, Madrid, Spain
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16
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Long P, Samnakay P, Jenner P, Rose S. A yeast two-hybrid screen reveals that osteopontin associates with MAP1A and MAP1B in addition to other proteins linked to microtubule stability, apoptosis and protein degradation in the human brain. Eur J Neurosci 2012; 36:2733-42. [DOI: 10.1111/j.1460-9568.2012.08189.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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17
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Effects of Heparin on Synaptic Activity in the Hemorrhagic Stroke Model in Vitro. Bull Exp Biol Med 2012; 152:684-7. [DOI: 10.1007/s10517-012-1606-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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18
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Abstract
Midkine (MK) is a heparin-binding growth factor involved in various cellular processes such as cellular proliferation, survival, and migration. In addition to these typical growth factor activities, MK exhibits several other activities related to fibrinolysis, blood pressure, host defense and other processes. Many cell-surface receptors have been identified to account for the multiple biological activities of MK. The expression of MK is frequently upregulated in many types of human carcinoma. Moreover, blood MK levels are closely correlated with patient outcome. Knockdown and blockade of MK suppress tumorigenesis and tumor development. Thus, MK serves as a tumor marker and a molecular target for cancer therapy. Furthermore, there is growing evidence that MK plays pivotal roles in neural and inflammatory diseases. Understanding of the mechanisms of action of MK is expected to create new therapeutic options for several human diseases.
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Affiliation(s)
- Kazuma Sakamoto
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
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19
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Asai H, Morita S, Miyata S. Effect of pleiotrophin on glutamate-induced neurotoxicity in cultured hippocampal neurons. Cell Biochem Funct 2011; 29:660-5. [DOI: 10.1002/cbf.1802] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Revised: 07/15/2011] [Accepted: 07/28/2011] [Indexed: 11/11/2022]
Affiliation(s)
- Hitomi Asai
- Department of Applied Biology; Kyoto Institute of Technology; Sakyo-ku; Kyoto; Japan
| | - Shoko Morita
- Department of Applied Biology; Kyoto Institute of Technology; Sakyo-ku; Kyoto; Japan
| | - Seiji Miyata
- Department of Applied Biology; Kyoto Institute of Technology; Sakyo-ku; Kyoto; Japan
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20
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Taravini IR, Chertoff M, Cafferata EG, Courty J, Murer MG, Pitossi FJ, Gershanik OS. Pleiotrophin over-expression provides trophic support to dopaminergic neurons in parkinsonian rats. Mol Neurodegener 2011; 6:40. [PMID: 21649894 PMCID: PMC3130680 DOI: 10.1186/1750-1326-6-40] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2010] [Accepted: 06/07/2011] [Indexed: 01/15/2023] Open
Abstract
Background Pleiotrophin is known to promote the survival and differentiation of dopaminergic neurons in vitro and is up-regulated in the substantia nigra of Parkinson's disease patients. To establish whether pleiotrophin has a trophic effect on nigrostriatal dopaminergic neurons in vivo, we injected a recombinant adenovirus expressing pleiotrophin in the substantia nigra of 6-hydroxydopamine lesioned rats. Results The viral vector induced pleiotrophin over-expression by astrocytes in the substantia nigra pars compacta, without modifying endogenous neuronal expression. The percentage of tyrosine hydroxylase-immunoreactive cells as well as the area of their projections in the lesioned striatum was higher in pleiotrophin-treated animals than in controls. Conclusions These results indicate that pleiotrophin over-expression partially rescues tyrosine hydroxylase-immunoreactive cell bodies and terminals of dopaminergic neurons undergoing 6-hydroxydopamine-induced degeneration.
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Affiliation(s)
- Irene Re Taravini
- Laboratorio de Parkinson Experimental, Instituto de Investigaciones Farmacológicas (ININFA-CONICET-UBA), Ciudad Autónoma de Buenos Aires, Argentina.
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21
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Muramatsu H, Yokoi K, Chen L, Ichihara-Tanaka K, Kimura T, Muramatsu T. Midkine as a factor to counteract the deposition of amyloid β-peptide plaques: in vitro analysis and examination in knockout mice. Int Arch Med 2011; 4:1. [PMID: 21223602 PMCID: PMC3024247 DOI: 10.1186/1755-7682-4-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Accepted: 01/12/2011] [Indexed: 12/31/2022] Open
Abstract
Background Midkine is a heparin-binding cytokine involved in cell survival and various inflammatory processes. Midkine accumulates in senile plaques of patients with Alzheimer's disease, while it counteracts the cytotoxic effects of amyloid β-peptide and inhibits its oligomerization. The present study was conducted to understand the role of midkine upon plaque formation of amyloid β-peptide. Methods A surface plasmon assay was performed to determine the affinity of midkine for amyloid β-peptide. The deposition of amyloid β-peptide was compared in the brain of wild-type and midkine-deficient mice. An effect of midkine to microglias was examined by cell migration assay. Results Midkine bound to amyloid β-peptide with the affinity of 160 nM. The C-terminal half bound to the peptide more strongly than the N-terminal half, and heparin inhibited midkine from binding to the peptide. Pleiotrophin, which has about 50% sequence identity with midkine also bound to amyloid β-peptide. The deposition of amyloid β-peptide plaques in the cortex and hippocampus was more intense in 15-month-old midkine-deficient mice, compared to the corresponding wild-type mice. Midkine promoted migration of microglias in culture. Conclusions These results are consistent with the view that midkine attenuates the deposition of amyloid β-peptide plaques, and thus progression of Alzheimer's disease, by direct binding and also by promoting migration of microglias.
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Affiliation(s)
- Hisako Muramatsu
- Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
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22
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Muramatsu T. Midkine: a promising molecule for drug development to treat diseases of the central nervous system. Curr Pharm Des 2011; 17:410-23. [PMID: 21375488 PMCID: PMC3267162 DOI: 10.2174/138161211795164167] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Accepted: 03/01/2011] [Indexed: 12/17/2022]
Abstract
Midkine (MK) is a heparin-binding cytokine, and promotes growth, survival, migration and other activities of target cells. After describing the general properties of MK, this review focuses on MK and MK inhibitors as therapeutics for diseases in the central nervous system. MK is strongly expressed during embryogenesis especially at the midgestation period, but is expressed only at restricted sites in adults. MK expression is induced upon tissue injury such as ischemic brain damage. Since exogenously administered MK or the gene transfer of MK suppresses neuronal cell death in experimental systems, MK has the potential to treat cerebral infarction. MK might become important also in the treatment of neurodegenerative diseases such as Alzheimer's disease. MK is involved in inflammatory diseases by enhancing migration of leukocytes, inducing chemokine production and suppressing regulatory T cells. Since an aptamer to MK suppresses experimental autoimmune encephalitis, MK inhibitors are promising for the treatment of multiple sclerosis. MK is overexpressed in most malignant tumors including glioblastoma, and is involved in tumor invasion. MK inhibitors may be of value in the treatment of glioblastoma. Furthermore, an oncolytic adenovirus, whose replication is under the control of the MK promoter, inhibits the growth of glioblastoma xenografts. MK inhibitors under development include antibodies, aptamers, glycosaminoglycans, peptides and low molecular weight compounds. siRNA and antisense oligoDNA have proved effective against malignant tumors and inflammatory diseases in experimental systems. Practical information concerning the development of MK and MK inhibitors as therapeutics is described in the final part of the review.
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Affiliation(s)
- Takashi Muramatsu
- Department of Health Science, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi 470-0195, Japan.
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23
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Kalus I, Salmen B, Viebahn C, von Figura K, Schmitz D, D'Hooge R, Dierks T. Differential involvement of the extracellular 6-O-endosulfatases Sulf1 and Sulf2 in brain development and neuronal and behavioural plasticity. J Cell Mol Med 2010; 13:4505-21. [PMID: 20394677 PMCID: PMC4515066 DOI: 10.1111/j.1582-4934.2008.00558.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The extracellular sulfatases Sulf1 and Sulf2 remove specific 6-O-sulfate groups from heparan sulfate, thereby modulating numerous signalling pathways underlying development and homeostasis. In vitro data have suggested that the two enzymes show functional redundancy. To elucidate their in vivo functions and to further address the question of a putative redundancy, we have generated Sulf1- and Sulf2-deficient mice. Phenotypic analysis of these animals revealed higher embryonic lethality of Sulf2 knockout mice, which can be associated with neuroanatomical malformations during embryogenesis. Sulf1 seems not to be essential for developmental or postnatal viability, as mice deficient in this sulfatase show no overt phenotype. However, neurite outgrowth deficits were observed in hippocampal and cerebellar neurons of both mutant mouse lines, suggesting that not only Sulf2 but also Sulf1 function plays a role in the developing nervous system. Behavioural analysis revealed differential deficits with regard to cage activity and spatial learning for Sulf1- and Sulf2-deficient mouse lines. In addition, Sulf1-specific deficits were shown for synaptic plasticity in the CA1 region of the hippocampus, associated with a reduced spine density. These results reveal that Sulf1 and Sulf2 fulfil non-redundant functions in vivo in the development and maintenance of the murine nervous system.
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Affiliation(s)
- Ina Kalus
- Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany
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24
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Muramatsu T. Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2010; 86:410-425. [PMID: 20431264 PMCID: PMC3417803 DOI: 10.2183/pjab.86.410] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2009] [Accepted: 02/24/2010] [Indexed: 05/29/2023]
Abstract
Midkine is a heparin-binding cytokine or a growth factor with a molecular weight of 13 kDa. Midkine binds to oversulfated structures in heparan sulfate and chondroitin sulfate. The midkine receptor is a molecular complex containing proteoglycans. Midkine promotes migration, survival and other activities of target cells. Midkine has about 50% sequence identity with pleiotrophin. Mice deficient in both factors exhibit severe abnormalities including female infertility. In adults, midkine is expressed in damaged tissues and involved in the reparative process. It is also involved in inflammatory reactions by promoting the migration of leukocytes, induction of chemokines and suppression of regulatory T cells. Midkine is expressed in a variety of malignant tumors and promotes their growth and invasion. Midkine appears to be helpful for the treatment of injuries in the heart, brain, spinal cord and retina. Midkine inhibitors are expected to be effective in the treatment of malignancies, rheumatoid arthritis, multiple sclerosis, renal diseases, restenosis, hypertension and adhesion after surgery.
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Affiliation(s)
- Takashi Muramatsu
- Department of Health Science, Faculty of Psychological and Physical Science, Aichi Gakuin University. 12 Araike, Aichi, Japan.
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25
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Abstract
CNS synapse assembly typically follows after stable contacts between "appropriate" axonal and dendritic membranes are made. We show that presynaptic boutons selectively form de novo following neuronal fiber adhesion to beads coated with poly-d-lysine (PDL), an artificial cationic polypeptide. As demonstrated by atomic force and live confocal microscopy, functional presynaptic boutons self-assemble as rapidly as 1 h after bead contact, and are found to contain a variety of proteins characteristic of presynaptic endings. Interestingly, presynaptic compartment assembly does not depend on the presence of a biological postsynaptic membrane surface. Rather, heparan sulfate proteoglycans, including syndecan-2, as well as others possibly adsorbed onto the bead matrix or expressed on the axon surface, are required for assembly to proceed by a mechanism dependent on the dynamic reorganization of F-actin. Our results indicate that certain (but not all) nonspecific cationic molecules like PDL, with presumably electrostatically mediated adhesive properties, can effectively bypass cognate and natural postsynaptic ligands to trigger presynaptic assembly in the absence of specific target recognition. In contrast, we find that postsynaptic compartment assembly depends on the prior presence of a mature presynaptic ending.
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26
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Piltonen M, Bespalov MM, Ervasti D, Matilainen T, Sidorova YA, Rauvala H, Saarma M, Männistö PT. Heparin-binding determinants of GDNF reduce its tissue distribution but are beneficial for the protection of nigral dopaminergic neurons. Exp Neurol 2009; 219:499-506. [DOI: 10.1016/j.expneurol.2009.07.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2008] [Revised: 06/15/2009] [Accepted: 07/07/2009] [Indexed: 12/17/2022]
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27
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Abstract
The role of extracellular matrix (ECM) in neurological development, function and degeneration has evolved from a simplistic physical adhesion to a system of intricate cellular signaling. While most cells require ECM adhesion to survive, it is now clear that differentiated function is intimately dependent upon cellular interaction with the ECM. Therefore, it is not surprising that the ECM is increasingly found to be involved in the enigmatic process of neurodegeneration. Descriptive studies of human neurodegenerative disorders and experimental studies of animal models of neurodegeneration have begun to define potential mechanisms of ECM disruption that can lead to synaptic and neuronal loss.
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Affiliation(s)
- Dafna Bonneh‐Barkay
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa
| | - Clayton A. Wiley
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa
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28
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Jin L, Jianghai C, Juan L, Hao K. Pleiotrophin and peripheral nerve injury. Neurosurg Rev 2009; 32:387-93. [DOI: 10.1007/s10143-009-0202-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2008] [Accepted: 02/14/2009] [Indexed: 01/11/2023]
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29
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Ohgake S, Shimizu E, Hashimoto K, Okamura N, Koike K, Koizumi H, Fujisaki M, Kanahara N, Matsuda S, Sutoh C, Matsuzawa D, Muramatsu H, Muramatsu T, Iyo M. Dopaminergic hypofunctions and prepulse inhibition deficits in mice lacking midkine. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:541-6. [PMID: 19217924 DOI: 10.1016/j.pnpbp.2009.02.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Revised: 02/08/2009] [Accepted: 02/08/2009] [Indexed: 02/04/2023]
Abstract
Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in various biological phenomena such as cell migration, neurogenesis, and tissue repair. We previously demonstrated that midkine-deficient (Mdk(-/-)) mice exhibited a delayed hippocampal development with impaired working memory and increased anxiety only at the age of 4 weeks. To assess whether midkine gene could play important roles in development and maintenance of central nervous system, we investigated biochemical and behavioral parameters in dopamine and glutamate neurotransmission of Mdk(-/-) mice. The Mdk(-/-) mice exhibited a hypodopaminergic state (i.e., decreased levels of dopamine and its receptors in the striatum) with no alterations of glutamatergic system (i.e., normal level of glutamate, glutamine, glycine, d-serine, l-serine, and NMDA receptors in the frontal cortex and hippocampus). We also found prepulse inhibition deficits reversed by clozapine and haloperidol in the Mdk(-/-) mice. Our results suggested that midkine deficiency may be related to neurochemical and behavioral dysfunctions in dopaminergic system.
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MESH Headings
- Acoustic Stimulation/methods
- Analysis of Variance
- Animals
- Behavior, Animal/drug effects
- Chromatography, High Pressure Liquid/methods
- Cytokines/deficiency
- Dopamine/metabolism
- Dopamine Antagonists/metabolism
- Dopamine Antagonists/pharmacology
- Dopamine Plasma Membrane Transport Proteins/metabolism
- Dose-Response Relationship, Drug
- Exploratory Behavior/physiology
- Interpersonal Relations
- Mice
- Mice, Inbred C57BL/metabolism
- Mice, Inbred DBA/metabolism
- Mice, Knockout
- Midkine
- Motor Activity/drug effects
- Motor Activity/genetics
- Neural Inhibition/drug effects
- Neural Inhibition/genetics
- Protein Binding/drug effects
- Protein Binding/genetics
- Radioligand Assay/methods
- Receptors, Dopamine D1/metabolism
- Receptors, Dopamine D2/metabolism
- Reflex, Startle/drug effects
- Reflex, Startle/genetics
- Tritium/metabolism
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Affiliation(s)
- Shintaro Ohgake
- Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan
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30
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Abstract
Most molecular and cellular studies of cognitive function have focused on either normal or pathological states, but recent research with transgenic mice has started to address the mechanisms of enhanced cognition. These results point to key synaptic and nuclear signalling events that can be manipulated to facilitate the induction or increase the stability of synaptic plasticity, and therefore enhance the acquisition or retention of information. Here, we review these surprising findings and explore their implications to both mechanisms of learning and memory and to ongoing efforts to develop treatments for cognitive disorders. These findings represent the beginning of a fundamental new approach in the study of enhanced cognition.
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Affiliation(s)
- Yong-Seok Lee
- Department of Neurobiology, Brain Research Institute, University of California, Los Angeles, California 90095, USA
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Brown TE, Wilson AR, Cocking DL, Sorg BA. Inhibition of matrix metalloproteinase activity disrupts reconsolidation but not consolidation of a fear memory. Neurobiol Learn Mem 2009; 91:66-72. [PMID: 18824238 PMCID: PMC2719776 DOI: 10.1016/j.nlm.2008.09.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2008] [Revised: 09/08/2008] [Accepted: 09/09/2008] [Indexed: 01/18/2023]
Abstract
The reconsolidation hypothesis posits that memories that have been reactivated can be either enhanced or disrupted by pharmacological manipulation. Synaptic plasticity is presumed to underlie the reconsolidation process. Matrix metalloproteinases are proteins that regulate the extracellular matrix involved in plasticity events, and these proteins have recently been shown to influence learning and memory. However, all studies on the role of matrix metalloproteinases in learning and memory have employed tasks that rely on contextual cues. The goal of this study was to determine the extent to which FN-439 would disrupt the consolidation and/or reconsolidation of a fear memory associated with a conditioned stimulus that signaled tone-shock pairings and that was independent of contextual cues. Male Sprague-Dawley rats were given infusions of FN-439 (35 microg intracerebroventricular) 30 min prior to conditioning (tone-shock paired association) or 30 min prior to a single reactivation session given 24h after conditioning. Administration of FN-439 did not disrupt consolidation of the freezing response when the tone (conditioned stimulus) was presented. In contrast, FN-439 infusion disrupted reconsolidation of the fear memory in a reactivation-dependent manner. The reduced freezing behavior was not due to a decrease in general anxiety levels, since FN-439 had no effect on the percent of open-arm time or open-arm entries in an elevated-plus maze task. Thus, we demonstrated for the first time that matrix metalloproteinase inhibition in the brain is capable of disrupting the reconsolidation of a tone-shock association memory that does not depend on contextual cues. The finding that a fear response to a previously paired conditioned stimulus can be disrupted by treatment with an MMP inhibitor during a single reactivation session suggests that this class of compounds may have therapeutic potential for posttraumatic stress disorder and/or simple phobias.
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Affiliation(s)
- Travis E. Brown
- Alcohol and Drug Abuse Research Program and Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, WA 99164-6520, USA
| | - Adrianne R. Wilson
- Alcohol and Drug Abuse Research Program and Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, WA 99164-6520, USA
| | - Davelle L. Cocking
- Department of Pharmacology/Toxicology, Washington State University, Pullman, WA 99164-6520, USA
| | - Barbara A. Sorg
- Alcohol and Drug Abuse Research Program and Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, WA 99164-6520, USA
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Jeong DG, Park WK, Park S. Artemin activates axonal growth via SFK and ERK-dependent signalling pathways in mature dorsal root ganglia neurons. Cell Biochem Funct 2008; 26:210-20. [PMID: 17868192 DOI: 10.1002/cbf.1436] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Artemin, one of the glial cell line-derived neurotrophic factor (GDNF) family, enhances the generation and survival of early sympathetic neurons and superior cervical ganglion (SCG) neurons. Src-family kinases (SFK) are involved in the growth and differentiation of cells, which are composed of unique Src homology 2 (SH2), Src homology 3 (SH3) and kinase domains. Various extra-cellular molecules containing growth factors and G-protein coupled receptors stimulate SFK. In this report, artemin is shown to have a significant effect on the neurite growth of dorsal root ganglia (DRG) neurons. Also, artemin triggers Src-family kinase activation and the phosphorylation of extra-cellular signal-regulated kinases (ERK) mitogen-activated protein kinase (MAPK). Artemin also regulated actin polymerization. There are several indications that another SH3-containing protein, Hck, and an SH3-containing adaptor protein, Nck1, play an important role in the organization of the actin cytoskeleton by cellular signalling. These findings suggest that the exploration of binding partners for the SH3 domain could provide an insight into regulation between the microtubule and actin networks. The binding partners for the SH3 domains of Nck, Src and Hck that we identified were Smc chromosome segregation ATPases, FOG Zn-finger protein and the FYVE zinc-binding domain, respectively.
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Affiliation(s)
- Doc Gyun Jeong
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, BK21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea
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Ferrario JE, Rojas-Mayorquín AE, Saldaña-Ortega M, Salum C, Gomes MZ, Hunot S, Raisman-Vozari R. Pleiotrophin receptor RPTP-ζ/β expression is up-regulated by l-DOPA in striatal medium spiny neurons of parkinsonian rats. J Neurochem 2008; 107:443-52. [DOI: 10.1111/j.1471-4159.2008.05640.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Properzi F, Lin R, Kwok J, Naidu M, van Kuppevelt TH, Ten Dam GB, Camargo LM, Raha-Chowdhury R, Furukawa Y, Mikami T, Sugahara K, Fawcett JW. Heparan sulphate proteoglycans in glia and in the normal and injured CNS: expression of sulphotransferases and changes in sulphation. Eur J Neurosci 2008; 27:593-604. [PMID: 18279312 DOI: 10.1111/j.1460-9568.2008.06042.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Heparan sulphate proteoglycans (HSPGs) have multiple functions relevant to the control of the CNS injury response, particularly in modulating the effects of growth factors and localizing molecules that affect axon growth. We examined the pattern of expression and glycanation of HSPGs in the normal and damaged CNS, and in astrocytes and oligodendrocyte precursors because of their participation in the injury reaction. The composition of HS glycosaminoglycan (GAG) chains was analysed by biochemical analysis and by the binding of antibodies that recognize sulphated epitopes. We also measured levels of HS sulphotransferases and syndecans. Compared with oligodendrocytes, oligodendrocyte precursors have more 2-O-sulphation in their HS GAG. This is accompanied by higher expression of the enzyme responsible for 2-O-sulphation, HS 2-O-sulphotransferase (HS2ST) and a fall in syndecan-1. Astrocytes treated with tumour growth factor (TGF)alpha or TGFbeta to mimic the injury response showed upregulation of syndecan-1 and HS2ST correlating with an increase in 2-O-sulphate residues in their HS GAGs. This also correlated with increased staining with AO4B08 anti-GAG antibody that recognizes high sulphation, and reduced staining with RB4EA12 recognizing low sulphation. After injury to the adult rat brain there was an overall increase in the quantity of HSPG around the injury site, mRNA for HS2ST was increased, and the changes in staining with sulphation-specific antibodies were consistent with an increase in 2-O-sulphated HS. Syndecan-1 was upregulated in astrocytes. The major injury-related change, seen in injured brain and cultured glia, was an increase in 2-O-sulphated HS and increased syndecan-1, suggesting novel approaches to modulating scar formation.
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Affiliation(s)
- Francesca Properzi
- Cambridge University Centre for Brain Repair, Robinson Way, Cambridge CB2 2PY, UK
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35
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Ezquerra L, Alguacil LF, Nguyen T, Deuel TF, Silos-Santiago I, Herradon G. Different pattern of pleiotrophin and midkine expression in neuropathic pain: correlation between changes in pleiotrophin gene expression and rat strain differences in neuropathic pain. Growth Factors 2008; 26:44-8. [PMID: 18365878 DOI: 10.1080/08977190801987711] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Pleiotrophin (PTN) and midkine (MK) are two growth factors highly redundant in function that exhibit neurotrophic actions and are upregulated at sites of nerve injury, both properties being compatible with a potential involvement in the pathophysiological events that follow nerve damage (i.e. neuropathic pain). We have tested this hypothesis by comparatively studying PTN and MK gene expression in the spinal cord and dorsal root ganglia (DRG) of three rat strains known to differ in their behavioural responses to chronic constriction injury (CCI) of the sciatic nerve: Lewis, Fischer 344 (F344) and Sprague-Dawley (SD). Real time RT-PCR revealed minimal changes in PTN/MK gene expression in the spinal cord after CCI despite the strain considered, but marked changes were detected in DRG. A significant upregulation of PTN gene expression occurred in injured DRG of the F344 strain, the only strain that recovers from CCI-induced mechanical allodynia 28 days after surgery. In contrast, PTN was found to be downregulated in injured DRG of SD rats, the most sensitive strain in behavioural studies. These changes in PTN were not paralleled by concomitant modifications of MK gene expression. The results demonstrate previously unidentified differences between PTN and MK patterns of expression. Furthermore, the data suggest that upregulation of PTN, but not MK, could play an important role in the recovery from CCI.
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Affiliation(s)
- Laura Ezquerra
- Department of Molecular and Experimental Medicine and Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
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36
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Greco SJ, Rameshwar P. Enhancing effect of IL-1alpha on neurogenesis from adult human mesenchymal stem cells: implication for inflammatory mediators in regenerative medicine. THE JOURNAL OF IMMUNOLOGY 2007; 179:3342-50. [PMID: 17709551 DOI: 10.4049/jimmunol.179.5.3342] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Mesenchymal stem cells (MSCs) are mesoderm-derived cells, primarily resident in adult bone marrow. MSCs show lineage specificity in generating specialized cells such as stroma, fat, and cartilage. MSCs express MHC class II and function as phagocytes and APCs. Despite these immune-enhancing properties, MSCs also exert veto functions and show evidence for allogeneic transplantation. These properties, combined with ease in isolation and expansion, demonstrate MSCs as attractive candidates for tissue repair across allogeneic barriers. MSCs have also been shown to transdifferentiate in neuronal cells. We have reported expression of the neurotransmitter gene, Tac1, in MSC-derived neuronal cells, with no evidence of translation unless cells were stimulated with IL-1alpha. This result led us to question the potential role of immune mediators in the field of stem cell therapy. Using Tac1 as an experimental model, IL-1alpha was used as a prototypical inflammatory mediator to study functions on MSC-derived neuronal cells. Undifferentiated MSCs and those induced to form neurons were studied for their response to IL-1alpha and other proinflammatory cytokines using production of the major Tac1 peptide, substance P (SP), as readout. Although IL-1alpha induced high production of SP, a similar effect was not observed for all tested cytokines. The induced SP was capable of reuptake via its high-affinity NK1R and was found to stabilize IL-1R mRNA. IL-1alpha also enhanced the rate of neurogenesis, based on expression of neuronal markers and cRNA microarray analyses. The results provide evidence that inflammatory mediators need to be considered when deciding the course of MSC transplantation.
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Affiliation(s)
- Steven J Greco
- Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
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37
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Bellon A. New genes associated with schizophrenia in neurite formation: a review of cell culture experiments. Mol Psychiatry 2007; 12:620-9. [PMID: 17440437 DOI: 10.1038/sj.mp.4001985] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
New genes consistently associated with schizophrenia include NRG1, Akt, DISC-1 and dysbindin-1. Since these genes participate in neurotransmission, neuroplasticity and neurodevelopment it has not been easy to elucidate which of these roles are abnormal in patients with schizophrenia. Neurite formation is identified as a crucial stage in development, and it is proposed that a defect in neurite formation originating from abnormally encoded proteins by these new genes could be at least an in vitro marker that reflects the most consistent molecular and neuroanatomical findings in schizophrenia. A systematic review of the literature linking the process of neurite formation to genes with replicated evidence that supported their association with schizophrenia was conducted. In addition, an outline of the process of neurite formation was included. Neurite formation was shown to be induced by neuregulins, the product of the gene NRG1. The activation of Akt, a serine/threonine kinase, promoted neurite formation in six independent studies. Conversely, two studies found that Akt inhibits neurite outgrowth. Stronger evidence supporting an association with the new genes related to schizophrenia and neurite formation comes from DISC-1. Defects in DISC-1 protein were shown to directly alter the process of neurite formation. Dysbindin-1 has not yet been directly implicated in neurite outgrowth. These findings suggest that the proteins encoded by NRG1, Akt and DISC-1 are implicated in the process of neurite formation in cellular models as well as, at least in part, animal models during development. Abnormalities in this process could have potential etiologic implications for schizophrenia. Direct evidence, however, of abnormal neurite formation in patients with schizophrenia is still missing. Limitations to this model are identified.
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Affiliation(s)
- A Bellon
- Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
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38
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Wang Q, Zhang B, Xiong WC, Mei L. MuSK signaling at the neuromuscular junction. J Mol Neurosci 2007; 30:223-6. [PMID: 17192681 DOI: 10.1385/jmn:30:1:223] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/1999] [Revised: 11/30/1999] [Accepted: 11/30/1999] [Indexed: 11/11/2022]
Abstract
The neuromuscular junction (NMJ) is a peripheral cholinergic synapse that conveys signals from motor neurons to muscle cells (Sanes and Lichtman, 1999; Sanes and Lichtman, 2001). The formation of the NMJ requires communication between motoneurons and muscle fibers. Three molecules are essential for NMJ formation: agrin, MuSK, and rapsyn. MuSK appears to be involved in every aspect of NMJ development and maintenance. The paper reviews agrin-MuSK cascades and its potential cross talk with Wnt signaling pathways.
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Affiliation(s)
- Qiang Wang
- Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Department of Neurology, Medical College of Georgia, Augusta, GA, USA
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39
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Marchionini DM, Lehrmann E, Chu Y, He B, Sortwell CE, Becker KG, Freed WJ, Kordower JH, Collier TJ. Role of heparin binding growth factors in nigrostriatal dopamine system development and Parkinson's disease. Brain Res 2007; 1147:77-88. [PMID: 17368428 DOI: 10.1016/j.brainres.2007.02.028] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2006] [Revised: 11/11/2006] [Accepted: 02/06/2007] [Indexed: 11/17/2022]
Abstract
The developmental biology of the dopamine (DA) system may hold important clues to its reconstruction. We hypothesized that factors highly expressed during nigrostriatal development and re-expressed after injury and disease may play a role in protection and reconstruction of the nigrostriatal system. Examination of gene expression in the developing striatum suggested an important role for the heparin binding growth factor family at time points relevant to establishment of dopaminergic innervation. Midkine, pleiotrophin (PTN), and their receptors syndecan-3 and receptor protein tyrosine phosphatase beta/zeta, were highly expressed in the striatum during development. Furthermore, PTN was up-regulated in the degenerating substantia nigra of Parkinson's patients. The addition of PTN to ventral mesencephalic cultures augmented DA neuron survival and neurite outgrowth. Thus, PTN was identified as a factor that plays a role in the nigrostriatal system during development and in response to disease, and may therefore be useful for neuroprotection or reconstruction of the DA system.
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Affiliation(s)
- Deanna M Marchionini
- Dept. Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
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40
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Muramatsu H, Zou P, Kurosawa N, Ichihara-Tanaka K, Maruyama K, Inoh K, Sakai T, Chen L, Sato M, Muramatsu T. Female infertility in mice deficient in midkine and pleiotrophin, which form a distinct family of growth factors. Genes Cells 2007; 11:1405-17. [PMID: 17121547 DOI: 10.1111/j.1365-2443.2006.01028.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Midkine and pleiotrophin form a family of growth factors. Mice deficient in one of the genes show few abnormalities on reproduction and development. To understand their roles in these processes, we produced mice deficient in both genes; the double deficient mice were born in only one third the number expected by Mendelian segregation and 4 weeks after birth weighed about half as much as wild-type mice. Most of the female double deficient mice were infertile. In these mice, the numbers of mature follicles and of ova at ovulation were reduced compared to numbers in wild-type mice. Both midkine and pleiotrophin were expressed in the follicular epithelium and granulosa cells of the ovary. The expression of these factors in the uterus was dramatically altered during the estrous cycle. The diestrus and proestrus periods were long and the estrus period was short in the double deficient mice, indicating the role of the factors in the estrous cycle. Furthermore, vaginal abnormality was found in about half of the double deficient mice. These abnormalities in combination resulted in female infertility. Therefore, midkine and pleiotrophin, together with their signaling receptors, play important roles in the female reproductive system.
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Affiliation(s)
- Hisako Muramatsu
- Department of Biochemistry, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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41
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Ezquerra L, Pérez-García C, Garrido E, Díez-Fernández C, Deuel TF, Alguacil LF, Herradón G. Morphine and yohimbine regulate midkine gene expression in the rat hippocampus. Eur J Pharmacol 2006; 557:147-50. [PMID: 17157293 DOI: 10.1016/j.ejphar.2006.11.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2006] [Revised: 11/07/2006] [Accepted: 11/08/2006] [Indexed: 10/23/2022]
Abstract
Pleiotrophin and midkine are two recently discovered growth factors that promote survival and differentiation of catecholaminergic neurons. Chronic opioid stimulation has been reported to induce marked alterations of the locus coeruleus-hippocampus noradrenergic pathway, an effect that is prevented when opioids are coadministered with the alpha2-adrenoceptor antagonist yohimbine. The present work tries to examine a possible link between yohimbine reversal of morphine effects and pleiotrophin/midkine activation in the rat hippocampus by studying the levels of expression of pleiotrophin and midkine in response to acute and chronic administration of morphine, yohimbine and combinations of both drugs. Pleiotrophin gene expression was not altered by any treatment; however midkine mRNA levels were increased after chronic treatment with morphine. Chronic administration of yohimbine alone also increased midkine expression levels, whereas yohimbine and morphine administered together exhibited summatory effects on the upregulation of midkine expression levels. The data suggest that midkine could play a role in the prevention of opioid-induced neuroadaptations in hippocampus by yohimbine.
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Affiliation(s)
- Laura Ezquerra
- Department of Molecular and Experimental Medicine and Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
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42
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Hienola A, Tumova S, Kulesskiy E, Rauvala H. N-syndecan deficiency impairs neural migration in brain. ACTA ACUST UNITED AC 2006; 174:569-80. [PMID: 16908672 PMCID: PMC2064262 DOI: 10.1083/jcb.200602043] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
N-syndecan (syndecan-3) is a transmembrane proteoglycan that is abundantly expressed in the major axonal pathways and in the migratory routes of the developing brain. When ligated by heparin-binding (HB) growth-associated molecule (GAM; pleiotrophin), N-syndecan mediates cortactin-Src kinase-dependent neurite outgrowth. However, the functional role of N-syndecan in brain development remains unexplored. In this study, we show that N-syndecan deficiency perturbs the laminar structure of the cerebral cortex as a result of impaired radial migration. In addition, neural migration in the rostral migratory stream is impaired in the N-syndecan-null mice. We suggest that the migration defect depends on impaired HB-GAM-induced Src kinase activation and haptotactic migration. Furthermore, we show that N-syndecan interacts with EGF receptor (EGFR) at the plasma membrane and is required in EGFR-induced neuronal migration.
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Affiliation(s)
- Anni Hienola
- Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland.
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43
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Zou P, Muramatsu H, Sone M, Hayashi H, Nakashima T, Muramatsu T. Mice doubly deficient in the midkine and pleiotrophin genes exhibit deficits in the expression of beta-tectorin gene and in auditory response. J Transl Med 2006; 86:645-53. [PMID: 16619002 DOI: 10.1038/labinvest.3700428] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
alpha-Tectorin and beta-tectorin are major noncollagenous proteins of the tectorial membrane, which plays a crucial role in the reception of sonic signals in the cochlea. Midkine and pleiotrophin are closely related proteins that serve as growth factors and cytokines. In mice doubly deficient in the midkine gene and pleiotrophin gene, expression of beta-tectorin mRNA was nearly abolished in the cochlea on day 1 and 7 after birth. Expression of alpha-tectorin mRNA was unaffected in the double knockout mice, and expression of beta-tectorin mRNA was not altered in mice deficient in only the midkine or pleiotrophin gene. In newborn wild-type mice, both midkine and pleiotrophin were expressed in the greater epithelial ridge of the cochlea, in which beta-tectorin mRNA was strongly expressed. These results indicate that either midkine or pleiotrophin is required for significant expression of beta-tectorin. In agreement with the view that beta-tectorin is essential for normal auditory function, mice doubly deficient in both midkine and pleiotrophin genes exhibited very severe auditory deficits. We observed that mice deficient in either midkine or pleiotrophin gene were also impaired in their auditory response, but the level of the deficit was generally low or moderate. The present finding illustrates the importance of growth factor expression in the cochlea for auditory function.
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Affiliation(s)
- Peng Zou
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan
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44
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Dityatev A, Frischknecht R, Seidenbecher CI. Extracellular matrix and synaptic functions. Results Probl Cell Differ 2006; 43:69-97. [PMID: 17068968 DOI: 10.1007/400_025] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Comprehensive analysis of neuromuscular junction formation and recent data on synaptogenesis and long-term potentiation in the central nervous system revealed a number of extracellular matrix (ECM) molecules regulating different aspects of synaptic differentiation and function. The emerging mechanisms comprise interactions of ECM components with their cell surface receptors coupled to tyrosine kinase activities (agrin, integrin ligands, and reelin) and interactions with ion channels and transmitter receptors (Narp, tenascin-R and tenascin-C). These interactions may shape synaptic transmission and plasticity of excitatory synapses either via regulation of Ca2+ entry and postsynaptic expression of transmitter receptors or via control of GABAergic inhibition. The ECM molecules, derived from both neurons and glial cells and secreted into the extracellular space in an activity-dependent manner, may also shape synaptic plasticity through setting diffusion constraints for neurotransmitters, trophic factors and ions.
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Affiliation(s)
- Alexander Dityatev
- Institut für Neurophysiologie und Pathophysiologie, Universitätsklinikum Hamburg-Eppendorf, Germany.
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45
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Reizes O, Clegg DJ, Strader AD, Benoit SC. A role for syndecan-3 in the melanocortin regulation of energy balance. Peptides 2006; 27:274-80. [PMID: 16289473 DOI: 10.1016/j.peptides.2005.02.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2004] [Accepted: 02/15/2005] [Indexed: 11/23/2022]
Abstract
Since the discovery that central melanocortin peptides play an important role in the control of body weight, an impressive amount of research has focused on understanding this complex neuroendocrine system. However, this research has also uncovered new complexities. One of these complexities is the recently discovered putative melanocortin "co-receptor," syndecan-3. In this review, we present an overview of the biology and potential functions of syndecan-3 and describe a novel hypothesis for its regulation of energy balance.
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Affiliation(s)
- Ofer Reizes
- Procter & Gamble Pharmaceuticals Inc. Health Care Research Center, Mason, OH 45040, USA
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46
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Abstract
The neuromuscular junction (NMJ) is a complex structure that serves to efficiently communicate the electrical impulse from the motor neuron to the skeletal muscle to signal contraction. Over the last 200 years, technological advances in microscopy allowed visualization of the existence of a gap between the motor neuron and skeletal muscle that necessitated the existence of a messenger, which proved to be acetylcholine. Ultrastructural analysis identified vesicles in the presynaptic nerve terminal, which provided a beautiful structural correlate for the quantal nature of neuromuscular transmission, and the imaging of synaptic folds on the muscle surface demonstrated that specializations of the underlying protein scaffold were required. Molecular analysis in the last 20 years has confirmed the preferential expression of synaptic proteins, which is guided by a precise developmental program and maintained by signals from nerve. Although often overlooked, the Schwann cell that caps the NMJ and the basal lamina is proving to be critical in maintenance of the junction. Genetic and autoimmune disorders are known that compromise neuromuscular transmission and provide further insights into the complexities of NMJ function as well as the subtle differences that exist among NMJ that may underlie the differential susceptibility of muscle groups to neuromuscular transmission diseases. In this review we summarize the synaptic physiology, architecture, and variations in synaptic structure among muscle types. The important roles of specific signaling pathways involved in NMJ development and acetylcholine receptor (AChR) clustering are reviewed. Finally, genetic and autoimmune disorders and their effects on NMJ architecture and neuromuscular transmission are examined.
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Affiliation(s)
- Benjamin W Hughes
- Department of Neurology, Case Western University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA
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47
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Lee CW, Peng HB. Mitochondrial clustering at the vertebrate neuromuscular junction during presynaptic differentiation. ACTA ACUST UNITED AC 2006; 66:522-36. [PMID: 16555236 DOI: 10.1002/neu.20245] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
During vertebrate neuromuscular junction (NMJ) development, presynaptic motor axons differentiate into nerve termini enriched in synaptic vesicles (SVs). At the nerve terminal, mitochondria are also concentrated, but how mitochondria become localized at these specialized domains is poorly understood. This process was studied in cultured Xenopus spinal neurons with mitochondrion-specific probe MitoTracker and SV markers. In nerve-muscle cocultures, mitochondria were concentrated stably at sites where neurites and muscle cells formed NMJs, and mitochondria coclustered with SVs where neurites were focally stimulated by beads coated with growth factors. Labeling with a mitochondrial membrane potential-dependent probe JC-1 revealed that these synaptic mitochondria were with higher membrane potential than the extrasynaptic ones. At early stages of bead-stimulation, actin-based protrusions and microtubule fragmentation were observed in neurites at bead contact sites, suggesting the involvement of cytoskeletal dynamics and rearrangement during presynaptic differentiation. Treating the cultures with an actin polymerization blocker, latrunculin A (Ltn A), almost completely abolished the formation of actin-based protrusions and partially inhibited bead-induced mitochondrial and SV clustering, whereas the microtubule disrupting agent nocodazole was ineffective in inhibiting the clustering of mitochondria and SVs. Lastly, in contrast to Ltn A, which blocked bead-induced clustering of both mitochondria and SVs, the ser/thr phosphatase inhibitor okadaic acid inhibited SV clustering but not mitochondrial clustering. These results suggest that at developing NMJs, synaptogenic stimuli induce the clustering of mitochondria together with SVs at presynaptic terminals in an actin cytoskeleton-dependent manner and involving different intracellular signaling molecules.
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Affiliation(s)
- Chi Wai Lee
- Department of Biology, the Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
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Mourlevat S, Debeir T, Ferrario JE, Delbe J, Caruelle D, Lejeune O, Depienne C, Courty J, Raisman-Vozari R, Ruberg M. Pleiotrophin mediates the neurotrophic effect of cyclic AMP on dopaminergic neurons: analysis of suppression-subtracted cDNA libraries and confirmation in vitro. Exp Neurol 2005; 194:243-54. [PMID: 15899261 DOI: 10.1016/j.expneurol.2005.02.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2004] [Revised: 02/22/2005] [Accepted: 02/24/2005] [Indexed: 11/21/2022]
Abstract
To better understand the particular vulnerability of mesencephalic dopaminergic neurons to toxins or gene mutations causing parkinsonism, we have taken advantage of a primary cell culture system in which these neurons die selectively. Antimitotic agents, such as cytosine arabinoside or cAMP, prevent the death of the neurons by arresting astrocyte proliferation. To identify factors implicated in either the death of the dopaminergic neurons or in the neuroprotective effect of cAMP, we constructed cDNA libraries enriched by subtractive hybridization and suppressive PCR in transcripts that are preferentially expressed in either control or cAMP-treated cultures. Differentially expressed transcripts were identified by hybridization of the enriched cDNAs with a commercially available cDNA expression array. The proteoglycan receptors syndecan-3 and the receptor protein tyrosine phosphatase zeta/beta were found among the transcripts preferentially expressed under control conditions, and their ligand, the cytokine pleiotrophin, was highly represented in the cDNA libraries for both conditions. Since pleiotrophin is expressed during embryonic and perinatal neural development and following lesions in the adult brain, we investigated its role in our cell culture model. Pleiotrophin was not responsible for the death of dopaminergic neurons under control conditions, or for their survival in cAMP-treated cultures. It was, however, implicated in the initial and cAMP-dependent enhancement of the differentiation of the dopaminergic neurons in our cultures. In addition, our experiments have provided evidence for a cAMP-dependent regulatory pathway leading to protease activation, and the identification of pleiotrophin as a target of this pathway.
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Affiliation(s)
- Sophie Mourlevat
- INSERM U679, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France
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Bampton ETW, Taylor JSH. Effects of Schwann cell secreted factors on PC12 cell neuritogenesis and survival. ACTA ACUST UNITED AC 2005; 63:29-48. [PMID: 15702477 DOI: 10.1002/neu.20119] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We have used PC12 cells to examine the effects of factors secreted by Schwann cells that promote cell survival and neurite outgrowth, and hence are likely candidates for promoting neuronal regeneration. RT-PCR showed that primary Schwann cells produced a range of neurotrophins, excluding NT3, but this profile was different from either of two cell lines SCTM41 or PVGSCSV40T, or forskolin-expanded Schwann cells. The effects of Schwann cell conditioned media on neurite outgrowth was tested against a range of factors, and showed clear neuritogenic effects. Of the factors tested, only NGF had a significant response on neuritogenesis. Western blotting for neurofilaments showed that primary Schwann cells induced a strong response close to that of NGF. The Trk tyrosine kinase inhibitor K252a did not block the neuritogenic effects of primary Schwann cells. In contrast, K252a blocked both NGF and the SCTM41 cell effects. Schwann cell conditioned media also enhanced PC12 cell survival. Again, in contrast with NGF or SCTM41 cells, the primary Schwann cell effect was Trk tyrosine kinase independent. The Schwann cell conditioned medium contains a protein factor (greater than 12 kDa and broken down by trypsin treatment) with remarkable thermal stability (unaffected at 95 degrees C for 15 min) and the ability to bind heparin. Our results provide clear evidence that Schwann cells produce factors other than those already known to stimulate a neural phenotype in PC12 cells, and which thus have potential regeneration enhancing effects.
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Affiliation(s)
- E T W Bampton
- Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom
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Chang MH, Huang CJ, Hwang SPL, Lu IC, Lin CM, Kuo TF, Chou CM. Zebrafish heparin-binding neurotrophic factor enhances neurite outgrowth during its development. Biochem Biophys Res Commun 2004; 321:502-9. [PMID: 15358204 DOI: 10.1016/j.bbrc.2004.06.172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2004] [Indexed: 11/17/2022]
Abstract
Heparin-binding neurotrophic factor (HBNF) is a secreted heparin-binding protein containing highly basic and cysteine-rich amino acid residues. In this study, we cloned the full-length HBNF cDNA from zebrafish and determined its genomic structure by bioinformatics analysis. Zebrafish HBNF gene is composed of five exons and four introns spanning approximately 82kb. RT-PCR analysis revealed that zebrafish HBNF transcript was highly expressed in adult brain and intestine tissues while less in other tissues. During embryogenesis, zebrafish HBNF transcript was observed to be moderately expressed at earlier stages with a gradual decline. Higher expression level was observed after hatching and maintaining this level into adulthood. The overall amino acid sequence of zebrafish HBNF shows 60% identity to human HBNF, but with approximately 40% identity to other midkine proteins. Like mammalian homolog, zebrafish HBNF could induce significant neurite outgrowth in PC12 cells without NGF stimulation. In addition, zebrafish HBNF was able to enhance extensive neurite outgrowth in zebrafish embryos during embryogenesis. In summary, a feasible in vivo assay for neurite outgrowth was established in zebrafish.
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Affiliation(s)
- Ming-Huang Chang
- Graduate Institute of Veterinary Medicine, National Taiwan University, Taipei, Taiwan, ROC
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