FEEDBACK REGULATION OF NEUROGENESIS IN MAMMALS

哺乳动物神经发生的反馈调节

• 批准号: 7027673
• 负责人: ANNE LEIGHTON CALOF
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027673
• 关键词: apoptosis; cell differentiation; cell growth regulation; chemoreceptors; follistatin; gene interaction; genetic screening; genetically modified animals; immunofluorescence technique; in situ hybridization; laboratory mouse; nervous system regeneration; neurogenesis; olfactions; polymerase chain reaction; protein biosynthesis; respiratory epithelium; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Understanding the biology of neuron production is of fundamental importance if we are to understand the origins of, and develop therapies for, disabilities of the nervous system. Although much is known about the signals that stimulate neurogenesis in mammals, signals that cause neurogenesis to cease when the nervous system has attained its appropriate size remain poorly understood. Yet negative regulation of neurogenesis is likely to be important not only during development, but also later, when persistence of negative signals may inhibit neuron regeneration. The olfactory epithelium (OE) of the mouse is a unique model system for studying this negative regulation. Many aspects of neurogenesis characteristic of the rest of the nervous system only during embryonic development are recapitulated throughout life in the OE, where neurogenesis proceeds continuously. Moreover, OE neurogenesis is a regulated process that maintains the number of differentiated neurons (olfactory receptor neurons [ORNs]) at a particular level. Studies in vivo and in vitro suggest that a signal, produced by neuronal cells (progenitors and ORNs) within the OE, acts on progenitors to inhibit proliferation and generation of new ORNs. Preliminary experiments indicate that growth and differentiation factor 11 (GDF 11) has characteristics expected of this signal. This idea is supported by the patterns of expression of Gdf11 and its putative receptors; the effects of GDF 11 on cultured OE cells; and the phenotypes of induced mutations in Gdf11 and its inhibitor, follistatin (Fst). To test the hypothesis that GDF11 is a crucial negative regulator of neurogenesis in the OE, three specific aims will be pursued: (1) GDF1 l's action in regulating OE neurogenesis will be elucidated, using genetic and pharmacological approaches in vitro and in vivo; (2) the role of Fst in OE neurogenesis in vivo will be determined using genetic tests; and (3) models for how GDF11 and Fst work together (and potentially with other factors) to achieve feedback regulation of neurogenesis will be developed and tested. These studies will provide insights into the molecular mechanisms by which neuron number -- and therefore, ultimately, function -- are regulated during development and regeneration of the mammalian nervous system.

描述（由申请人提供）：如果我们要了解神经系统的残疾的起源并发展疗法，那么了解神经元产生的生物学至关重要。尽管对刺激哺乳动物神经发生的信号知之甚少，但是当神经系统达到其适当的大小时会导致神经发生停止的信号仍然很差。然而，神经发生的负调节不仅在发育过程中也很重要，而且后来，当负信号的持续性可能抑制神经元再生时。小鼠的嗅觉上皮（OE）是研究这种负调控的独特模型系统。神经发生的许多方面仅在胚胎发育过程中仅概括了神经发育过程中神经发生的整个生命，而神经发生不断进行。此外，OE神经发生是一个受调节的过程，该过程维持特定水平的分化神经元（嗅觉受体神经元[ORNS]）的数量。体内和体外的研究表明，OE内神经元细胞（祖细胞和ORN）产生的信号作用于祖细胞以抑制新ORN的增殖和产生。初步实验表明，生长和分化因子11（GDF 11）具有该信号的特征。 GDF11及其推定受体的表达模式支持了这个想法。 GDF 11对培养的OE细胞的影响；以及GDF11及其抑制剂Follistatin（FST）中诱导突变的表型。为了检验GDF11是OE中神经发生的至关重要的负调节剂的假设，将使用遗传学和药理方法在体外和体内使用遗传学和药理方法来阐明GDF1 L在调节OE神经发生方面的作用的三个具体目标； （2）将使用基因检测确定FST在体内OE神经发生中的作用； （3）将开发和测试GDF11和FST如何共同工作（可能与其他因素一起工作（可能与其他因素）进行反馈调节。这些研究将提供有关在哺乳动物神经系统的发育和再生过程中神经元数（最终，功能）的分子机制的见解。