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

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，大量复杂的神经元：这 过程称为神经发生。 多年来人们都知道 胚胎神经系统的神经发生随着发育逐渐减慢 进行，最终停止，因为神经元祖细胞最终产生 分化的神经元，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，提供了有关嗅觉上皮（OE）模型系统的线索 这种现象的基础：这些研究表明，差异化 嗅觉受体神经元（ORN）产生反馈信号 通过其自身的祖细胞抑制神经发生。 初步实验 表明骨形态发生蛋白 4 (BMP4)，TGFbeta 的成员 多肽生长因子超家族，模仿这种生长抑制 信号，并且 BMP4 在 OE 中高表达。 这些数据表明 BMP4 可能是 OE 中神经发生的重要负调节因子，并且 也许神经系统的其他区域也是如此。 来表征 BMP4对神经祖细胞抑制作用的细胞基础，以及 检验内源表达 BMP4 介导反馈的假设 抑制 OE 中的神经发生，以下具体目标将是 追求：（1）BMP4对ORN谱系祖细胞的作用 将使用组织培养测定来表征以确定对 祖细胞增殖、分化和凋亡； （2） BMP4 mRNA 和 BMP4 抑制蛋白的表达模式将被绘制 使用原位杂交技术进行 OE 组织切片和培养； (3) 内源性 BMP4 作为 OE 负调节因子的作用 体内神经发生将在转基因小鼠中进行测试，其中 BMP4 活动减少。 通过确定BMP4是否在反馈调节中发挥关键作用 神经发生，并通过表征该分子的细胞基础 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影响 在发育中的哺乳动物神经系统中。 该信息应提供 深入了解神经元时影响细胞更新的可能策略 由于疾病、受伤或衰老而丢失。