DRG Progenitor Cells: Role of Extrinsic & Intrinsic Cues

描述（由申请人提供）：背根神经节（DRG）的感觉神经元是一种异质细胞群，其支持多种形式，如疼痛、温度、触觉、压力和本体感受。然而，所有这些细胞都来自一个共同的神经上皮祖细胞库，这些祖细胞是从神经管中迁移出来的。细胞表型的多样性是如何建立的？在遗传性周围神经病中，这种发育顺序的某些方面会出错;有趣的是，通常只有特定的感觉神经元亚群缺乏。例如，家族性自主神经功能障碍的特点是介导疼痛和温度的感觉神经元减少。此外，在成人发作的周围神经病变中，DRG感觉神经元的特定子集退化。因此，为了开发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。外在的环境信号和可遗传的信号都控制着细胞表型的建立。因此，这个建议的目标是确定血统的作用，在确定的感觉神经元的亚类的身份，除了确定外在因素，调节这一过程。一个主要的悬而未决的问题是，是否有不同的亚类有丝分裂活跃的祖细胞内的新生DRG，产生离散亚型的感觉神经元。我们建议通过进行谱系分析来鉴定和表征DRG内祖细胞的亚型，并鉴定调节其增殖、存活和/或分化的外在因素。我们的实验室提供了强有力的证据，神经营养因子（NT-3），CNTF，PACAP和NELL 2在调节DRG祖细胞亚群的增殖和分化中的作用。然而，很明显，其他外在因素在DRG发育过程中起作用。基于它们在多个系统中的突出作用以及我们对其表达的初步研究，我们建议使用卵内错误表达分析来确定一类主要受体酪氨酸激酶家族（Axl/tyro 3/mer家族的鸡同源物：c-eyk和rek）在背根神经节发育过程中的功能。这些目标的实现将增强我们对神经组织内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.