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。尽管我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期间很重要，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。小鼠嗅上皮（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期间具有神经系统其余部分的特征，在OE的整个生命中都得到了再现，在OE中神经发生不断进行。此外，OE神经发生是一个受调控的过程，它将分化神经元（嗅觉受体神经元[orn]）的数量维持在一定水平。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，抑制新orn的增殖和生成。初步实验表明，生长与分化因子11 （GDF 11）具有该信号的特征。这一观点得到了Gdf11及其可能受体的表达模式的支持；GDF - 11对体外培养OE细胞的影响；Gdf11及其抑制剂卵泡抑素（Fst）诱导突变的表型。为了验证GDF11是OE中神经发生的关键负调节因子的假设，将实现三个具体目标：(1)通过体外和体内遗传学和药理学方法阐明GDF1在OE神经发生中的调节作用；(2) Fst在体内OE神经发生中的作用将通过基因检测来确定；(3)将开发和测试GDF11和Fst如何协同工作（以及可能与其他因素一起）以实现神经发生反馈调节的模型。这些研究将提供对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功能调控的分子机制的见解。

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.