FEEDBACK REGULATION OF NEUROGENESIS IN MAMMALS

描述（由申请人提供）：如果我们要了解神经系统残疾的起源和开发治疗方法，了解神经元产生的生物学是至关重要的。虽然我们对哺乳动物中刺激神经发生的信号了解很多，但当神经系统达到适当的大小时，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，而且在以后，当持续的负信号可能抑制神经元再生时也很重要。小鼠的嗅上皮（OE）是研究这种负调节的独特模型系统。神经系统其余部分仅在胚胎发育期间具有的神经发生特征的许多方面在OE中贯穿一生，神经发生持续进行。此外，OE神经发生是一个受调节的过程，其将分化的神经元（嗅觉受体神经元[ORNs]）的数量维持在特定水平。体内和体外研究表明，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）具有预期的这种信号的特征。Gdf 11及其假定受体的表达模式、GDF 11对培养的OE细胞的作用以及Gdf 11及其抑制剂卵泡抑素（Fst）诱导突变的表型支持了这一观点。为了检验GDF 11是OE中神经发生的关键负调节剂的假设，将追求三个具体目标：（1）将使用体外和体内遗传和药理学方法阐明GDF 11在调节OE神经发生中的作用;（2）将使用遗传测试确定Fst在体内OE神经发生中的作用;以及（3）将开发和测试GDF 11和Fst如何一起工作（以及潜在地与其他因素一起）以实现神经发生的反馈调节的模型。这些研究将提供深入了解神经元数量的分子机制-因此，最终，功能-在哺乳动物神经系统的发育和再生过程中受到调节。

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.