A p75/Ret receptor complex as an integrator of survival and death

p75/Ret 受体复合物作为生存和死亡的整合者

• 批准号: 10093143
• 负责人: Brian Anthony Pierchala
• 金额: $ 44.84万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10093143
• 关键词: Adult; Afferent Neurons; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Apoptotic; Automobile Driving; Brain-Derived Neurotrophic Factor; CASP8 gene; CASP9 gene; Cell Death; Cell Line; Cell surface; Cells; Cessation of life; Complex; Development; Disease; Family; GDNF receptors; Grant; Growth; Growth Factor; Huntington Disease; In Vitro; Ligands; Link; Lysosomes; Mediating; Mediator of activation protein; Membrane Microdomains; Molecular; Motor Neurons; Mus; Nerve Growth Factors; Nervous System Trauma; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropilin-1; Neurotrophic Tyrosine Kinase Receptor Type 1; Nociceptors; Pathogenesis; Pathway interactions; Play; Process; Protein Tyrosine Kinase; Proteolysis; Receptor Activation; Receptor Signaling; Recycling; Regulation; Role; Semaphorin-3A; Signal Transduction; Spinal; Structure of superior cervical ganglion; Synapses; TNF gene; Testing; Therapeutic Agents; Treatment Protocols; Withdrawal; axon guidance; base; deprivation; experimental study; glial cell-line derived neurotrophic factor; in vivo; inhibitor/antagonist; member; mouse genetics; nerve supply; neurogenesis; neurotrophic factor; proto-oncogene protein c-ret; receptor; release factor; secretase; small molecule inhibitor; somatosensory; transcriptional coactivator p75

Throughout the developing nervous system excess neurons are generated which are nonessential, or inappropriately connected, and are eliminated by programmed cell death (PCD). In the PNS, the extent of apoptosis is governed by both a limited supply of survival-promoting neurotrophic factors provided by targets of innervation, and by apoptosis-inducing competition factors secreted by “winning neurons” that have successfully competed for these neurotrophic factors. The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are a family of potent growth factors that support the survival of autonomic, somatosensory and spinal motor neurons. The GFLs promote survival and growth through a common signal-transducing receptor tyrosine kinase, Ret. During this grant period we discovered that Ret interacts with p75, a member of the TNF family of death receptors, and p75 enhances GDNF-mediated Ret activation and survival. When p75 is deleted specifically in sensory neurons, approximately 20% are lost between P14 and adulthood, and these losses selectively occur in Ret+ nonpeptidergic nociceptors. These results indicate that p75 is required for the development of the nonpeptidergic nociceptor lineage by fine-tuning Ret-mediated trophic support. We also found that during PCD in sympathetic neurons of the superior cervical ganglion (SCG) Ret is restricted to a subset of degenerating neurons that rapidly undergo apoptosis. Pro-apoptotic conditions induce the association of Ret with p75, thereby enhancing the regulated intramembrane proteolysis (RIP) cleavage of p75 and activation of downstream apoptotic effectors. Deletion of p75 in Ret+ neurons, and deletion of Ret, specifically during PCD, inhibits apoptosis both in vitro and in vivo. These results indicate that Ret acts non-canonically to augment p75-mediated apoptosis. The molecular mechanisms that underlie the ability of p75 to enhance Ret signaling, and for Ret to enhance p75 mediated death, are not well understood, and are the subject of Aim 1. We also discovered recently that semaphorin 3A (Sema3A), a secreted repulsive axon guidance molecule, induces apoptosis of primary SCG neurons, and that deletion of its receptor components, Neuropilin-1 (Npn-1) and PlexinA3 (PA3), significantly reduce PCD in the SCG. Sema3A induces apoptosis via the extrinsic pathway, requiring caspase-8, as opposed to the intrinsic pathway triggered by NGF withdrawal in sympathetic neurons that requires caspase-9. The combination of apoptosis induced by neurotrophic factor deprivation and death receptor activation in the developing SCG raises the question of the extent to which caspase-8 and caspase-9 contribute to apoptosis during PCD, and which death receptors are driving this process. These questions will be the subject of Aim 2. Collectively the experiments proposed here will define the molecular mechanisms and magnitude of the role played by death receptor pathways, such as Npn-1/PA3 and p75, in PCD.

在整个神经系统发育过程中，产生了多余的非必需神经元， 不适当的连接，并通过程序性细胞死亡（PCD）消除。在PNS中， 细胞凋亡的发生既受有限的促进存活的神经营养因子的供应所控制， 神经支配的靶点，以及由“获胜神经元”分泌的诱导竞争因子， 成功地竞争了这些神经营养因子。胶质细胞源性神经营养因子 GDNF家族配体（GFL）是一个支持肿瘤细胞存活的强效生长因子家族。 自主神经元、躯体感觉神经元和脊髓运动神经元。GFLs通过以下方式促进生存和生长： 一种常见的信号转导受体酪氨酸激酶，Ret。在这段时间里，我们发现， Ret与死亡受体TNF家族成员p75相互作用，p75增强GDNF介导的Ret激活和存活。当p75在感觉神经元中特异性缺失时， 在P14和成年期之间大约20%的损失，并且这些损失选择性地发生在Ret+非肽能伤害感受器中。这些结果表明，p75是发育所必需的。 非肽能伤害感受器谱系的微调RET介导的营养支持。我们还发现 在上级颈神经节（SCG）交感神经元的PCD期间，Ret仅限于一个子集 退化的神经元迅速发生凋亡。促凋亡条件诱导 Ret与p75的结合，从而增强受调节的膜内蛋白水解（RIP）切割 p75和下游凋亡效应物的激活。Ret+神经元中p75的缺失， Ret，特别是在PCD过程中，抑制细胞凋亡在体外和体内。这些结果表明 Ret非典型地增加p75介导的细胞凋亡。其背后的分子机制 p75增强Ret信号传导能力和Ret增强p75介导的死亡的能力并不好 这是我们的目标，也是目标1的主题。我们最近还发现，semaphorin 3A（Sema 3A）， 一种分泌的排斥性轴突导向分子，诱导原代SCG神经元凋亡， 其受体成分Neuropilin-1（Npn-1）和PlexinA 3（PA 3）的缺失显著降低PCD 在SCG。Sema 3A通过外源性途径诱导细胞凋亡，需要caspase-8，而不是 由交感神经元中需要半胱天冬酶-9的NGF撤回触发的内在途径。的 神经营养因子剥夺和死亡受体激活诱导的细胞凋亡 发展中的SCG提出了一个问题，即caspase-8和caspase-9在多大程度上有助于 PCD过程中的细胞凋亡，以及哪些死亡受体在驱动这一过程。这些问题将是 目标2的主题。总的来说，这里提出的实验将定义分子机制， 死亡受体途径如Npn-1/PA 3和p75在PCD中所起作用的大小。