Genetic Regulation of Neural Crest Neurocongenesis

描述（由申请人提供）：如何从最初同质的细胞群中产生不同的细胞命运是发育神经生物学中的一个基本问题。神经嵴就是这样一个细胞群，它能够产生一系列令人难以置信的衍生物。像皮肤中的色素细胞或周围神经系统中的神经元和神经胶质细胞一样，功能和形式不同的细胞都来自神经嵴。研究，以了解一个特定的细胞类型，背根神经节（DRG）感觉神经元的规格，提出。转录因子Ngn 1对DRG特化至关重要。我们已经开发了一种转基因系，其中DRG前体由ngnl控制元件调节的GFP表达标记。我们建议使用这条线来了解参与DRG规格的调节途径。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。我们还将跟踪神经嵴形成停止后很长时间内从潜伏前体中添加新的DRG神经元。此外，正向遗传筛选已经确定了三个改变DRG发育的突变。我们建议描述突变位点的作用，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其他突变。了解感觉神经元的发育可能最终有助于设计治疗方法，以改善神经退行性疾病，糖尿病相关感觉神经病变和疼痛疾病患者的功能。

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.