神经干细胞的命运决定机制及其靶点调控的研究进展

神经药理学报 ›› 2012, Vol. 2 ›› Issue (3): 37-42.

神经干细胞的命运决定机制及其靶点调控的研究进展

马寅仲^{1,2 ，陈乃宏¹}

1.天然药物活性物质与功能国家重点实验室，新药作用机制研究与药效评价北京市重点实验室,中国医学科学院药物研究所，北京，100050，中国
2.天津中医药大学，天津，300193，中国

出版日期:2012-06-26 发布日期:2013-12-25
通讯作者: 陈乃宏，Tel.: +86-010-63165177，Fax: +86-010-63165177，E-mail: chennh@imm.ac.cn
作者简介:马寅仲，男，硕士研究生；研究方向：神经干细胞分化；E-mail：damama_da@126.com
基金资助:
国家863计划基金（No.2012AA020303），长江学者和创新团队发展计划(PCSIRT No.IRT1007)，国家自然科学基金（No.81274122、No.81173578），国家国际科技合作项目(No.2010DFB32900)，创新药物研究开发技术平台建设（No.2012ZX09301002-004、No.2012ZX09103101-006），教育部博士点基金重点项目(No.20121106130001)，北京市自然基金重点项目(No.7131013)

Research Advances on Fate Decision of NSCs and Its Potential Target Modulation

MA Yin-zhong^1,2, CHEN Nai-hong¹

1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
2. Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China

Online:2012-06-26 Published:2013-12-25
Contact: 陈乃宏，Tel.: +86-010-63165177，Fax: +86-010-63165177，E-mail: chennh@imm.ac.cn
About author:马寅仲，男，硕士研究生；研究方向：神经干细胞分化；E-mail：damama_da@126.com
Supported by:
国家863计划基金（No.2012AA020303），长江学者和创新团队发展计划(PCSIRT No.IRT1007)，国家自然科学基金（No.81274122、No.81173578），国家国际科技合作项目(No.2010DFB32900)，创新药物研究开发技术平台建设（No.2012ZX09301002-004、No.2012ZX09103101-006），教育部博士点基金重点项目(No.20121106130001)，北京市自然基金重点项目(No.7131013)

摘要/Abstract

摘要： 神经干细胞（neural stem cells, NSCs）是哺乳动物神经系统中神经元、星型胶质细胞、少突胶质细胞的分化来源。近年来对于NSCs的增殖与分化机制及其在临床治疗神经退行性疾病的研究在世界范围内引起了学者们的极大兴趣。多种细胞调节因子存在于微环境中共同调节NSCs的自我更新、迁移及分化。其中Notch通路，NF-κB通路与Wnt通路尤其作为NSCs发育中的“命运决定者”而受到广泛的关注。它们中的每条通路均具有独自控制分化与增殖的能力。本文针对Notch通路、Wnt通路以及NF-κB通路对NSCs增殖与分化的作用机制进行了归纳与阐述，对其中潜在的药物作用靶点与目前最新的内、外源化合物对NSCs增殖与分化的作用进行了总结，希望对今后神经再生方面的研究提供理论指导。

关键词: 神经干细胞, 命运决定, Notch, Wnt, NF-kB

Abstract: Neural stem cells (NSCs) are the source of neurons, oligodendrocytes and astrocytes in mammal neural system. In recent years, study base on the mechanisms of NSCs differentiation，proliferation and clinic research on neural degeneration diseases have been held great interests. Multiple cell regulation factors in the microenvironment co-regulate the self-renewal, differentiation and migration of NSCs. Among the factors, Notch，NF-κB and Wnt have been called “fate decision makers” and gained extensive attention. Each of them can control either differentiation or proliferation on their own. Here we reviewed the mechanisms of fate decision of three major signaling pathways: Notch, Wnt and NF-kB and summarized the potential drug targets and exogenous regulation factors, hoping to provide some guidance for future stem cell research.

Key words: neural stem cell, fate decision, notch, wnt, NF-kB

中图分类号:

R964

马寅仲, 陈乃宏. 神经干细胞的命运决定机制及其靶点调控的研究进展[J]. 神经药理学报, 2012, 2(3): 37-42.

MA Yin-zhong, CHEN Nai-hong. Research Advances on Fate Decision of NSCs and Its Potential Target Modulation[J]. ACTA NEUROPHARMACOLOGICA, 2012, 2(3): 37-42.

参考文献

[1] David J Anderson. Stem cells and pattern formation in the nervous system: the possible versus the actual [J]. Neuron, 2001, 30(1): 19-35.

[2] Fred H Gage. Mammalian neural stem cells [J]. Science, 2000, 287(5457): 1433-1438.

[3] McKay R. Stem cells in the central nervous system [J]. Science, 1997, 276(5309): 66-71.

[4] Zhang Yong-gang, Liu Jian-jun, Yao Shao-hua. Nuclear factor kappa B signaling initiates early differentiation of neural stem cells [J]. Stem Cells, 2012, 30(3): 510-524.

[5] Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling [J]. Science, 1995, 268(5208): 225-232.

[6] Iva Greenwald. Structure/function studies of lin-12/Notch proteins [J]. Curr Opinion Gen Dev, 1994, 4(4): 556-562.

[7] Kristi A Wharton, Kristen M Johansen, Xu Tian, et al. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats [J]. Cell, 1985, 43(3 Pt 2): 567-581.

[8] José Luis de la Pompa, Andrew Wakeham, Kristen M.Correia, et al. Conservation of the Notch signalling pathway in mammalian neurogenesis [J]. Development, 1997, 124(6): 1139-1148.

[9] Keilani Serene, Healey Delacy, Sugaya Kiminobu. Reelin regulates differentiation of neural stem cells by activation of notch signaling through Disabled-1 tyrosine phosphorylation [J]. Can J Physiol Pharmacol, 2012, 90(3): 361-369.

[10] Roshan Tofighi, Wan Norhamidath Wan Ibrahim, Paola Rebellato, Non–dioxin-like polychlorinated biphenyls interfere with neuronal differentiation of embryonic neural stem cells [J]. Toxicol Sci, 2011, 124(1):192-201.

[11] Luc Grandbarbe, Julien Bouissac, Matt Rand, Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process [J]. Development, 2003, 130(7): 1391-1402.

[12] Hiromi Shimojo, Toshiyuki Ohtsuka, Ryoichiro Kageyama. Dynamic expression of Notch signaling genes in neural stem/progenitor cells [J]. Front Neurosci, 2011, 5:78.

[13] Raphael Kopan, Ma Xenia Ilagan. The canonical Notch signaling pathway: unfolding the activation mechanism [J]. Cell, 2009, 137(2): 216-233.

[14] Daniel M Tremmel, Sedat Resad, Christopher J Little, et al. Notch and PKC are involved in formation of the lateral region of the dorso-ventral axis in drosophila embryos [J]. PLoS One, 2013, 8(7): e67789.

[15] Luc Grandbarbe, Julien Bouissac, Matt Rand, et al. Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process [J]. Development, 2003, 130(7): 1391-1402.

[16] Nicolas Bertrand, Diogo S Castro, Francois Guillemot. Proneural genes and the specification of neural cell types [J]. Nat Rev Neurosci, 2002, 3(7): 517–530.

[17] Sarah E Ross, Michael E Greenberg, Charles D Stiles. Basic helix-loop-helix factors in cortical development [J]. Neuron, 2003, 39(1): 13–25.

[18] Chi Zhi-kai, Zhang Jian-min, Akinori Tokunaga, Botch promotes neurogenesis by Antagonizing Notch. Dev Cell [J]. Dev Cell, 2012, 22(4):707-720.

[19] Luca Tiberi, Jelle van den Ameele, Jordane Dimidschstein. BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets [J]. Nat Neurosci, 2012, 15(12):1627-1635.

[20] Randall T Moon. Wnt/beta-catenin pathway [J]. Sci STKE, 2005, doi: 10.1126/stke.2712005cm1.

[21] Randall T Moon, Aimee D Kohn, Giancarlo V De Ferrari, et al. Wnt and beta-catenin signalling: diseases and therapies [J]. Nat Rev Genet, 2004, 5(9): 691–701.

[22] Teo Jia-Ling, Kahn Michael. The Wnt signaling pathway in cellular proliferation and differentiation: A tale of two coactivators [J]. Adv Drug Deliv Rev, 2010, 62(12):1149-1155.

[23] Maiyon Park, Randall T. Moon, The planar cell-polarity gene stbm regulates cell behavior and cell fate in vertebrate embryos [J]. Nat Cell Biol, 2001, 4(1): 20–25.

[24] Wang Yan-shu, Jeremy Nathan. Tissue/planar cell polarity in vertebrates: new insights and new questions [J]. Development, 2007, 134 (4): 647–658.

[25] Aimee D Kohn, Randall T Moon, Wnt and calcium signaling: beta-catenin-independent pathways [J]. Cell Calcium, 2005, 38(3-4): 439–446.

[26] Hsien-Yu Wang, Craig C Malbon. Wnt signaling, Ca2+, and cyclic GMP: visualizing Frizzled functions [J]. Science, 2003, 300(5625): 1529–1530.

[27] Lin Tian, Liu Yang-feng, Shi Ming. Promotive effect of ginsenoside Rd on proliferation of neural stem cells in vivo and in vitro [J]. J Ethnopharmacol, 2012, 142(3): 754-761.

[28] In Tag Yu, Sang-Hun Lee, Yong-Sung Lee, et al. Differential effects of corticosterone and dexamethasone on hippocampal neurogenesis in vitro [J]. Biochem Biophys Res Commun, 2004, 317(2): 484-490.

[29] Julie A Siegenthaler, Amir M Ashique, Konstantinos Zarbalis. Retinoic acid from the meninges regulates cortical neuron generation [J]. Cell, 2009, 139(3): 597-609.

[30] Sharon Amit, Ada Hatzubai, Yaara Birman, et al. Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway [J]. Genes Dev, 2002, 16(9): 1066–1076.

[31] Catriona Y Logan, Roel Nusse, The Wnt signaling pathway in development and disease [J]. Annu Rev Cell Dev Biol, 2004, 20: 781–810.

[32] Chen Bei-Yu, Wang Xi, Wang Zhao-Yan. Brain-derived neurotrophic factor stimulates proliferation and differentiation of neural stem cells, possibly by triggering the Wnt/b-Catenin signaling pathway [J]. J Neurosci Res, 2013, 91(1):30-41.

[33] Stephane Angers, Randall T Moon. Proximal events in Wnt signal transduction [J]. Nat Rev Mol Cell Biol, 2009, 10 (7): 468–477.

[34] Alexander Aulehla, Christian Wehrle, Beate Brand-Saberi, et al. Wnt3a plays a major role in the segmentation clock controlling somitogenesis [J]. Dev Cell, 2003, 4(3): 395-406.

[35] J G Rodríguez-González, M Santillán, A C Fowler, et al. The segmentation clock in mice: interaction between the Wnt and Notch signalling pathways [J]. J Theor Biol, 2007, 248(1): 37-47.

[36] Tomoyuki Miyabayashi, Jia-Ling Teo, Masashi Yamamoto, et al. Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency [J]. Proc. Natl Acad. Sci, 2007,104(13): 5668-5673.

[37] Katayoon H Emami, Cu Nguyen, Hong Ma, et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected] [J]. Proc Natl Acad Sci, 2004, 101(34): 12682-12687.

[38] Wu Jia-ying, Pan Zong-fu, Cheng Mei-yuan. Ginsenoside Rg1 facilitates neural differentiation of mouse embryonic stem cells via GR-dependent signaling pathway [J]. Neurochem Int, 2013, 62(1): 92-102.

[39] Ning Na, Hu Jin-Feng, Sun Jian-Dong. (-)Clausenamide facilitates synaptic transmission at hippocampal Schaffer collateral-CA1 synapses [J]. Eur J Pharmacol, 2012, 682(1-3): 50-55.

[40] Nicholas P Whitney, Tess M Eidem, Peng Hui, et al. Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders [J]. J Neurochem, 2009, 108(6): 1343-1359.

[41] Cheryl A Kassed, Miles Herkenham. NF-kappaB p50-deficient mice show reduced anxiety-like behaviors in tests of exploratory drive and anxiety [J]. Behav Brain Res, 2004, 154(2): 577-584.

[42] Mollie K Meffert, Jolene M Chang, Brian J Wiltgen, et al. NF-kappa B functions in synaptic signaling and behavior [J]. Nat Neurosci, 2003, 6(10): 1072-1078.

[43] Vincent F.S Shih, Jeffrey D Kearns, Soumen Basak, et al. Kinetic control of nega-tive feedback regulators of NF-kappaB/RelA determines their pathogen- and cytokine-receptor signaling specificity [J]. Proc Natl Acad Sci USA, 2009, 106(24): 9619-9624.

[44] Shomyseh Sanjabi, Kevin J Williams, Simona Saccani, et al. A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation [J]. Genes Dev, 2005, 19(18): 2138-2151.

[45] Sulagna Das, Anirban Basu. Inflammation: a new candidate in modulating adult neurogenesis [J]. J Neurosci Res, 2008, 86(6): 1199-1208.

[46] Liu Bin, Randy Yang, Kelly A Wong, et al. Negative regulation of NF-kappaB signaling by PIAS1 [J]. Mol Cell Biol, 2005, 25(3): 1113-1123.

[47] Ingrid E Wertz, Karen M O’Rourke, Zhou Honglin, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling [J]. Nature, 2004, 430(7000): 694-699.