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并开发治疗方法，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，但当神经系统达到合适的大小时，导致神经发生停止的信号仍然知之甚少。然而，对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，当负信号的持续可能会抑制神经元再生时也是如此。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的整个生命过程中被概括，在那里神经发生持续进行。此外，OE神经发生是一个调节过程，将分化的神经元(嗅觉感受器神经元[Ons])的数量维持在特定水平。体内和体外的研究表明，OE内的神经细胞(祖细胞和ON)产生的信号作用于祖细胞，抑制新ON的增殖和生成。初步实验表明，生长和分化因子11(GDF11)具有该信号的预期特征。Gdf11及其可能的受体的表达模式、GDF11对培养的OE细胞的影响以及Gdf11及其抑制物卵泡抑素(Fst)诱导突变的表型支持了这一观点。为了验证GDF11是OE中神经发生的关键负调控因子的假设，我们将追求三个具体目标：(1)GDF1 L在调节OE神经发生中的作用将通过体外和体内的遗传学和药理学方法来阐明；(2)Fst在OE体内神经发生中的作用将通过基因测试来确定；以及(3)GDF11和Fst如何协同(并可能与其他因素一起)实现神经发生的反馈调控的模型将被开发和测试。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--从而最终调节功能--的分子机制的洞察力。

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.