Genetic Regulation of Neural Crest Neurocongenesis

描述（由申请人提供）：如何从最初的同质细胞群中产生不同的细胞命运是发育神经生物学的一个基本问题。神经嵴就是这样一种细胞群，它能够产生一系列令人难以置信的衍生物。皮肤中的色素细胞、周围神经系统的神经元和胶质细胞等功能和形态各异的细胞都来源于神经嵴。研究，以了解具体的细胞类型，背根神经节（DRG）感觉神经元的规格，提出。转录因子Ngn1对DRG规范至关重要。我们已经开发了一种转基因系，其中DRG前体被ngnl控制元件调控的GFP表达标记。我们建议使用这条线来理解DRG规范中涉及的监管途径。我们将研究Notch信号通路在调节感觉神经元细胞数量中的作用。我们还将在神经嵴形成停止后很长一段时间内追踪来自潜伏前体的新DRG神经元的添加。此外，一项正向遗传筛查已经确定了三种改变DRG发育的突变。我们建议描述突变作用的位点，并确定潜在的分子病变。最后，我们提出了一种新的筛选方法来识别额外的突变。了解感觉神经元的发育可能最终有助于设计改善神经退行性疾病、糖尿病相关感觉神经病变和疼痛障碍患者功能的治疗方法。

DESCRIPTION (provided by applicant): How distinct cell fates are generated from initially homogeneous cell populations is a fundamental question in developmental neurobiology. The neural crest is one such cell population that is capable of producing an incredible array of derivatives. Cells as different in function and form as the pigment cells in the skin or the neurons and glia of the peripheral nervous system are all derived from neural crest. Studies to understand the specification of a specific cell type, dorsal root ganglion (DRG) sensory neurons, are proposed. The transcription factor Ngn1 is critical for DRG specification. We have developed a transgenic line where DRG precursors are marked by GFP expression regulated by ngnl control elements. We propose to use this line to understand the regulatory pathways involved in DRG specification. We will examine the roles of the Notch signaling pathway in regulating sensory neuron cell number. We will also follow the addition of new DRG neurons from latent precursors long after neural crest formation has ceased. In addition, a forward genetic screen has identified three mutations that alter DRG development. We propose to characterize the locus of mutation action and identify the underlying molecular lesions. Finally, we propose a new screen to identify additional mutations. Understanding sensory neuron development may eventually help in the design of therapies for improving function in patients affected with neurodegenerative diseases, diabetes-related sensory neuropathy, and pain disorders.