DRG Progenitor Cells: Role of Extrinsic & Intrinsic Cues

描述(申请人提供)：背根神经节(DRG)的感觉神经元是一个不同的细胞群体，它伴随着不同的形式，如疼痛、温度、触摸、压力和本体感觉。然而，所有这些细胞都来自一个共同的神经上皮祖细胞池，这些神经上皮祖细胞从神经管中迁出。这种细胞表型的多样性是如何建立起来的？在遗传性周围神经病中，这种发育序列的某些方面出现了问题；有趣的是，通常只有特定的感觉神经元亚群缺乏。例如，家族性自主神经障碍的特点是负责调节疼痛和温度的感觉神经元减少。此外，在成人起病的周围神经病中，DRG感觉神经元的特定亚群退化。因此，需要阐明构成每个感觉神经元亚类发展的关键事件，以便制定针对特定受损亚群的治疗策略。外在的、环境的信号和可遗传的信号都支配着细胞表型的建立。因此，这一提议的目的是确定谱系在确定感觉神经元亚类的身份中的作用，以及确定调控这一过程的外部因素。一个主要的悬而未决的问题是，在新生的背根节中是否存在不同的有丝分裂活跃的祖细胞亚类，从而产生不同亚型的感觉神经元。我们建议通过进行谱系分析来鉴定和表征驻留在DRG内的祖细胞亚型，并鉴定调控其增殖、存活和/或分化的外在因素。我们的实验室已经为神经营养因子(NT-3)、CNTF、PACAP和NELL2在调节DRG前体细胞亚群的增殖和分化中的作用提供了强有力的证据。然而，很明显，其他外在因素在DRG的发育过程中也起作用。基于它们在多种系统中的重要作用和我们对其表达的初步研究，我们建议使用OVO误表达分析来确定一类主要的受体酪氨酸激酶家族--AX1/Tyro3/mer家族的鸡同系物：C-Eyk和rek在DRG发育过程中的功能。这些目标的实现将加强我们对NeuRA组织中不同细胞类型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.