Dorsal Root Ganglia Progenitor Cells: Role of Extrinsic & Intrinsic Cues

描述（由申请人提供）：背根神经节（DRG）的感觉神经元是一个异质细胞群，服务于疼痛、温度、触觉、压力和本体感觉等多种模式。然而，所有这些细胞都来自一个共同的神经上皮祖细胞池，这些祖细胞来自神经管。细胞表型的多样性是如何建立的？在遗传性周围神经病变中，这种发育顺序的各个方面出错；有趣的是，通常只有特定的感觉神经元亚群有缺陷。例如，家族性自主神经障碍的特征是调节疼痛和温度的感觉神经元减少。此外，在成人发病的周围神经病变中，DRG感觉神经元的特定亚群退化。因此，为了制定针对特定受损亚群的治疗策略，需要阐明包括每个感觉神经元亚类发育的关键事件。外部环境信号和遗传信号共同控制着细胞表型的形成。因此，除了确定调节这一过程的外在因素外，本提案的目标是确定谱系在确定感觉神经元亚类身份方面的作用。一个主要的悬而未决的问题是，在新生DRG中是否存在不同的有丝分裂活性祖细胞亚类，从而产生不同的感觉神经元亚型。我们建议通过进行谱系分析来鉴定和表征居住在DRG中的祖细胞亚型，并确定调节其增殖、存活和/或分化的外在因素。我们的实验室已经提供了强有力的证据，证明神经营养因子（NT-3）、CNTF、PACAP和NELL2在调节DRG祖细胞亚群的增殖和分化中的作用。然而，很明显，在DRG发展过程中，其他外在因素也在起作用。基于它们在多个系统中的突出作用和我们对其表达的初步研究，我们建议使用蛋错误表达分析来确定一类主要的受体酪氨酸激酶家族，Axl/tyro3/mer家族的鸡同源物：c-eyk和rek在DRG发育过程中的功能。这些目标的实现将增强我们对神经组织中离散细胞类型的发生和分化的细胞和分子机制的理解。

DESCRIPTION (provided by applicant): The sensory neurons of the dorsal root ganglia (DRG) are a heterogeneous cell population that subserve such diverse modalities as pain, temperature, touch, pressure and proprioception. Yet all of these cells derive from a common pool of neuroepithelial progenitors which emigrate from the neural tube. How is such diversity in cell phenotype established? In hereditary peripheral neuropathies, aspects of this developmental sequence go awry; intriguingly, often only specific subsets of sensory neurons are deficient. For example, Familial Dysautonomia is marked by a diminution in the sensory neurons that mediate pain and temperature. Furthermore, in adult onset peripheral neuropathies, specific subsets of DRG sensory neurons degenerate. Thus an elucidation of the critical events which comprise the development of each sensory neuron subclass is required in order to develop therapeutic strategies for targeting the specific compromised subpopulation. Both extrinsic, environmental signals and inheritable cues govern the establishment of cell phenotype. Thus the goal of this proposal is to determine the role of lineage in determining the identity of subclasses of sensory neurons in addition to identifying the extrinsic factors which regulate this process. A major outstanding question is whether there are distinct subclasses of mitotically-active progenitor cells within the nascent DRG that give rise to discrete subtypes of sensory neurons. We propose to identify and characterize the subtypes of progenitor cells resident within the DRG by conducting a lineage analysis, and to identify the extrinsic factors that regulate their proliferation, survival, and/or differentiation. Our lab has provided strong evidence for a role for neurotrophins (NT-3), CNTF, PACAP and NELL2 in regulating the proliferation and differentiation of subsets of DRG progenitor cells. However, it is evident that other extrinsic factors are operative during DRG development. Based on their prominent role in multiple systems and our preliminary investigations of their expression, we propose to determine the function of a major class of receptor tyrosine kinase family, the chick homologues of Axl/tyro3/mer family: c-eyk and rek, during DRG development using in ovo misexpression analyses. Fulfillment of these aims will enhance our understanding of the cellular and molecular mechanisms that sculpt the genesis and differentiation of discrete cell types within a neura tissue.