Mechanisms of apoptotic neuron clearance in the peripheral nervous system

描述（由申请人提供）：在哺乳动物神经系统的正常发育过程中，存在广泛的程序性细胞死亡，这是建立适当的细胞数量和连接所必需的。许多病理学，例如神经损伤和阿尔茨海默病等疾病也可能导致细胞凋亡。由此产生的神经元尸体必须被有效去除，以防止免疫系统反应，这可能涉及炎症和自身免疫。事实上，许多自身免疫性疾病与未能正确清除死亡细胞有关。不幸的是，人们对这种吞噬过程的分子机制知之甚少，特别是在神经系统中。在周围神经系统中，对于如何清除死亡神经元几乎一无所知。因此，本研究的总体目标是阐明发育中的周围神经系统中凋亡神经元吞噬作用的细胞和分子机制。在秀丽隐杆线虫中，两条参与凋亡细胞清除的途径已被基因定义：第一个包括 CED-1、-6、-7 和 -10，第二个包括 CED-2、-5、-10 和 -12。大多数这些基因的哺乳动物同源物已被鉴定；然而，对于被认为具有细胞尸体受体功能的CED-1，已经提出了几种可能的同源物，包括MEGF10、LRP-1和清道夫受体SREC，但尚未达成共识。这些途径是否参与哺乳动物发育过程中凋亡神经元的清除尚不清楚。我们的初步数据表明，MEGF10 和相关蛋白 Jedi 是背根神经节 (DRG) 神经元吞噬所必需的，并且神经节中的卫星细胞表达这些基因并负责清除死亡神经元。因此，我们假设卫星细胞在胚胎发生过程中对死亡 DRG 神经元的吞噬作用涉及假定的 CED-1 同源物 MEGF10 和 Jedi。为了解决这一假设，我们提出以下具体目标：（1）确定 MEGF10 和/或 Jedi 是否作为卫星细胞吞噬凋亡神经元的受体发挥作用； (2) 明确MEGF10和Jedi在发育小鼠中的表达模式； (3)确定Jedi或MEGF10信号是否通过CED-1途径的同源物来调节Rac； (4)确定发育过程中神经元尸体吞噬是否需要体内需要Jedi。阐明凋亡神经元被吞噬的机制不仅将增强我们对哺乳动物神经系统发育的理解，而且可能为自身免疫性神经病的病因学提供重要的见解。

DESCRIPTION (provided by applicant): During the normal development of the mammalian nervous system there is extensive programmed cell death, which is required for establishing proper cell numbers and connections. A number of pathologies, such as nerve injury and diseases such as Alzheimer's can lead to apoptosis as well. The resulting neuronal corpses must be efficiently removed in order to prevent an immune system response, which can involve inflammation and autoimmunity. Indeed, a number of autoimmune diseases have been associated with a failure to properly clear dead cells. Unfortunately, the molecular mechanisms underlying this phagocytic process are poorly understood, particularly in the nervous system. In the peripheral nervous system, there is virtually nothing known about how the dead neurons are removed. Hence, the overall goal of this study is to elucidate the cellular and molecular mechanisms underlying the phagocytosis of apoptotic neurons in the developing peripheral nervous system. In C. elegans, two pathways involved in apoptotic cell clearance have been genetically defined; the first includes CED-1, -6, -7 and -10 and the second CED-2, -5, -10 and -12. The mammalian homologs of most of these genes have been identified; however, for CED-1, which is thought to function as a receptor for cell corpses, there have been several possible homologs proposed, including MEGF10, LRP-1 and the scavenger receptor SREC, but no consensus has been reached. Whether these pathways participate in the removal of apoptotic neurons during mammalian development is not known. Our preliminary data suggest that MEGF10 and a related protein, Jedi, are required for dorsal root ganglia (DRG) neuron engulfment and that satellite cells in the ganglia express these genes and are responsible for the removal of the dead neurons. Therefore, we hypothesize that the phagocytosis of dead DRG neurons during embryogenesis by satellite cells involves the putative CED-1 homologs MEGF10 and Jedi. To address this hypothesis we propose the following specific aims: (1) Determine whether MEGF10 and/or Jedi functions as a receptor for apoptotic neuron engulfment by satellite cells; (2) Define the expression pattern of MEGF10 and Jedi in the developing mouse; (3) Determine whether Jedi or MEGF10 signal through homologs of the CED-1 pathway to regulate Rac; (4) Determine whether Jedi is required in vivo for neuronal corpse engulfment during development. Elucidating the mechanisms by which apoptotic neurons are phagocytosed will not only enhance our understanding of the development of the mammalian nervous system, but will likely provide important insights into the etiology of autoimmune neuropathies.