DRG Progenitor Cells: Role of Extrinsic & Intrinsic Cues

DRG 祖细胞：外在的作用

• 批准号: 6895096
• 负责人: Frances Lefcort
• 金额: $ 26.89万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895096
• 关键词: biological signal transduction; cell differentiation; cell proliferation; chick embryo; immunocytochemistry; in situ hybridization; nerve stem cell; neural crest; neuregulins; neurogenesis; neurons; neurotrophic factors; polymerase chain reaction; protein tyrosine kinase; receptor; spinal ganglion

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.

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种群，可提供诸如疼痛，温度，触摸，压力和本体感受等多种方式。然而，所有这些细胞都来自于从神经管移民的神经上皮祖细胞的常见池。细胞表型的这种多样性如何建立？在遗传周围神经病中，这种发育顺序的各个方面出现了。有趣的是，通常只有特定的感觉神经元子集缺乏缺乏。例如，家族性功能障碍的标志是介导疼痛和温度的感觉神经元的降低。此外，在成年发作外周神经病中，DRG感觉神经元的特定子集退化。因此，需要阐明构成每个感觉神经元子类发展的关键事件，以制定针对特定受损亚群的治疗策略。外部，环境信号和可继承的提示都决定了细胞表型的建立。因此，该提案的目的是确定谱系在确定感觉神经元子类别的身份中的作用，除了确定调节该过程的外部因素。一个主要的关注问题是，在新生DRG中是否存在有丝分裂活性祖细胞的不同亚类，从而引起感觉神经元的离散亚型。我们建议通过进行谱系分析来识别和表征DRG中祖细胞的亚型，并确定调节其增殖，存活和/或分化的外部因素。我们的实验室为神经营养蛋白（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提供了有力的证据。但是，很明显，其他外部因素在DRG开发过程中是可行的。基于它们在多个系统中的重要作用以及我们对其表达的初步研究，我们建议在使用OVO Misexpressions在DRG发育过程中确定主要的受体酪氨酸激酶家族的功能，AXL/Tyro3/MER家族的Chick/Tyro3/Mer家族的Chick Chick同源物：C-Eyk和Rek。这些目标的实现将增强我们对雕刻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。