FEEDBACK REGULATION OF NEUROGENESIS IN MAMMALS

哺乳动物神经发生的反馈调节

• 批准号: 6872464
• 负责人: ANNE LEIGHTON CALOF
• 金额: $ 34.64万
• 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/6872464
• 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残疾的起源并开发治疗方法，那么了解神经元产生的生物学至关重要。尽管人们对刺激哺乳动物神经发生的信号了解很多，但当神经系统达到适当大小时导致神经发生停止的信号仍然知之甚少。然而，神经发生的负调控可能不仅在发育过程中很重要，而且在发育后期也很重要，因为负信号的持续存在可能会抑制神经元再生。小鼠的嗅觉上皮（OE）是研究这种负调节的独特模型系统。仅在胚胎发育期间神经系统其余部分的神经发生特征的许多方面在 OE 中在整个生命过程中得到重述，其中神经发生不断进行。此外，OE 神经发生是一个受调节的过程，它将分化的神经元（嗅觉受体神经元 [ORN]）的数量维持在特定水平。体内和体外研究表明，OE 内的神经元细胞（祖细胞和 ORN）产生的信号作用于祖细胞，抑制增殖和新 ORN 的生成。初步实验表明生长和分化因子 11 (GDF 11) 具有该信号的预期特征。 Gdf11 及其假定受体的表达模式支持了这一想法； GDF 11 对培养的 OE 细胞的影响；以及 Gdf11 及其抑制剂卵泡抑素 (Fst) 诱导突变的表型。为了检验 GDF11 是 OE 神经发生的关键负调节因子这一假设，我们将追求三个具体目标：（1）使用体外和体内遗传和药理学方法阐明 GDF11 在调节 OE 神经发生中的作用； (2)使用基因测试确定Fst在体内OE神经发生中的作用； (3) 将开发和测试 GDF11 和 Fst 如何协同工作（并可能与其他因素一起）以实现神经发生的反馈调节的模型。这些研究将深入了解哺乳动物神经系统发育和再生过程中神经元数量（以及最终的功能）受到调节的分子机制。