FEEDBACK REGULATION OF NEUROGENESIS IN MAMMALS

哺乳动物神经发生的反馈调节

• 批准号: 2856636
• 负责人: ANNE LEIGHTON CALOF
• 金额: $ 21.87万
• 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 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856636
• 关键词: apoptosis; bone morphogenetic proteins; cell differentiation; cell growth regulation; genetically modified animals; in situ hybridization; laboratory mouse; neurogenesis; protein biosynthesis; respiratory epithelium; stem cells; tissue /cell culture; apoptosis; bone morphogenetic proteins; cell differentiation; cell growth regulation; genetically modified animals; in situ hybridization; laboratory mouse; neurogenesis; protein biosynthesis; respiratory epithelium; stem cells; tissue /cell culture

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.

描述（研究者的摘要）：结构和 哺乳动物神经系统的功能取决于一代， 在开发期间，大量复杂的神经元： 过程称为神经发生。 多年来已经知道 胚胎神经系统中的神经发生随着发育而逐渐减慢 收益，随着神经元祖细胞的终极产生，最终停止 分化的神经元，但是这种现象的分子基础是 未知。 但是，使用鼠标的最新研究 嗅觉上皮（OE）模型系统提供了有关该模型的线索 这种现象的基础：这些研究表明分化 嗅觉受体神经元（ORNS）产生一个信号，以回馈 抑制自己的祖细胞神经发生。 初步实验 表明骨形态发生蛋白4（BMP4），TGFBETA的成员 多肽生长因子的超家族，模仿这种生长抑制 信号，该BMP4在OE中高度表达。 这些数据表明 BMP4可能是OE中神经发生的关键负调节剂，并且 也许在神经系统的其他领域。 表征 BMP4S对神经元祖细胞的抑制作用的细胞基础，以及 为了测试内源表达的BMP4介导反馈的假设 抑制神经发生在OE中，以下特定目的将是 追捕：（1）BMP4对ORN谱系中祖细胞的作用 将使用组织培养测定法来确定对 祖细胞增殖，分化和凋亡死亡； （2） BMP4 mRNA和BMP4抑制蛋白的表达模式将被映射 在OE组织切片和培养物中，使用原位杂交技术； （3）内源性BMP4作为OE的负调节剂的作用 体内神经发生将在BMP4的转基因小鼠中进行测试 活动减少。 通过确定BMP4是否在反馈调节中起关键作用 神经发生，并通过表征该分子的细胞基础 行动，这些研究将提供重要的信息 对我们对生长控制分子基础的理解的影响 在发展中的哺乳动物神经系统中。 此信息应提供 洞悉神经元时影响细胞更新的可能策略 由于疾病，伤害或衰老而丢失。