Genetic Regulation of Neural Crest Neurocongenesis

描述(由申请人提供)：如何从最初相同的细胞群体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。神经脊就是这样一个细胞群体，它能够产生令人难以置信的一系列衍生品。无论是皮肤中的色素细胞，还是周围神经系统的神经元、神经胶质细胞，无论是功能和形态都不同的细胞都起源于神经沟。为了解一种特定细胞类型--背根神经节(DRG)感觉神经元的特性而进行的研究被提出。转录因子Ngn1对DRG的调控起着关键作用。我们已经建立了一种转基因株系，其中DRG前体通过受NGN1调控元件调控的GFP表达来标记。我们建议使用这条线来理解DRG规范中涉及的调控通路。我们将研究Notch信号通路在调节感觉神经细胞数量中的作用。我们还将关注在神经峰形成停止很久之后，来自潜在前体的新的DRG神经元的增加。此外，一项正向基因筛查发现了三种改变DRG发育的突变。我们建议表征突变作用的位置，并确定潜在的分子损伤。最后，我们提出了一种新的筛查方法来识别额外的突变。了解感觉神经元的发育最终可能有助于设计治疗方案，以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.