FEEDBACK REGULATION OF NEUROGENESIS IN MAMMALS

描述(调查者摘要)：结构的复杂性和 哺乳动物神经系统的功能取决于世代， 在发育过程中，一大类复杂的神经元： 这一过程被称为神经发生。多年来，人们已经知道 胚胎神经系统中的神经发生随着发育逐渐减慢 最终停止，因为神经元前体细胞产生了终末期 分化神经元，但这种现象的分子基础是 未知。然而，该实验室最近的研究，使用小鼠 嗅觉上皮(OE)模型系统，提供了一条关于 这一现象的基础：这些研究表明，分化 嗅觉感受器神经元(ON)产生的信号反馈给 通过自身的祖细胞抑制神经发生。初步实验 提示骨形态发生蛋白4(BMP4)是转化生长因子β的成员 多肽生长因子超家族，模拟这种生长抑制 BMP4在OE中高表达。这些数据表明 BMP4可能是OE中神经发生的关键负性调节因子，并且 也许在神经系统的其他区域也是如此。要刻画 BMP4对神经前体细胞抑制作用的细胞基础，以及 检验内源性表达的BMP4介导反馈的假设 在OE中抑制神经发生，将有以下具体目标 追踪：(1)BMP4在ORN谱系中对祖细胞的作用 将使用组织培养试验来确定对 祖细胞的增殖、分化和凋亡性死亡； BMP4mRNA和BMP4抑制蛋白的表达模式将被绘制出来 在OE组织切片和培养中使用原位杂交技术； (3)内源性BMP4作为OE的负调节因子的作用 体内神经发生将在含有BMP4的转基因小鼠中进行测试 活跃度降低。 通过确定BMP4是否在反馈调节中发挥关键作用 神经发生，并通过表征这种分子的细胞基础 行动，这些研究将提供具有重要意义的信息 对我们理解生长控制的分子基础的启示 在发育中的哺乳动物神经系统中。此信息应提供 对影响细胞更新的可能策略的洞察 因疾病、受伤或衰老而丢失。

DESCRIPTION (Investigator's Abstract): The complexity of structure and function of the mammalian nervous system is dependent on the generation, during development, of a large and complex assortment of neurons: this process is known as neurogenesis. It has been known for many years that neurogenesis in the embryonic nervous system gradually slows as development proceeds, eventually halting as neuronal progenitors give rise to terminally differentiated neurons, but the molecular basis of this phenomenon is unknown. However, recent studies in this laboratory, using the mouse olfactory epithelium (OE) model system, have provided a clue concerning the basis of this phenomenon: these studies indicate that differentiated olfactory receptor neurons (ORNs) produce a signal that feeds back to inhibit neurogenesis by their own progenitor cells. Preliminary experiments indicate that Bone Morphogenetic Protein 4 (BMP4), a member of the TGFbeta superfamily of polypeptide growth factors, mimics this growth inhibitory signal, and that BMP4 is highly expressed in OE. These data suggest that BMP4 may be a crucial negative regulator of neurogenesis in the OE, and perhaps in other areas of the nervous system as well. To characterize the cellular basis of BMP4s inhibitory action on neuronal progenitor cells, and to test the hypothesis that endogenously expressed BMP4 mediates feedback inhibition of neurogenesis in the OE, the following specific aims will be pursued: (1) the actions of BMP4 on progenitor cells in the ORN lineage will be characterized using tissue culture assays to determine effects on progenitor cell proliferation, differentiation, and apoptotic death; (2) the expression patterns of BMP4 mRNA and BMP4 inhibitory proteins will be mapped in OE tissue sections and cultures using in situ hybridization techniques; and (3) a role for endogenous BMP4 as a negative regulator of OE neurogenesis in vivo will be tested in transgenic mice in which BMP4 activity is reduced. By determining whether BMP4 plays a key role in feedback regulation of neurogenesis, and by characterizing the cellular basis of this molecule's action, these studies will provide information that has important implications for our understanding of the molecular basis of growth control in the developing mammalian nervous system. This information should provide insights into possible strategies for effecting cell renewal when neurons have been lost due to disease, injury, or aging.