A p75/Ret Receptor Complex as an Integrator of Survival and Death

p75/Ret 受体复合体作为生存和死亡的整合者

• 批准号: 10612858
• 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/10612858
• 关键词: Acceleration; Adult; Afferent Neurons; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Apoptotic; Automobile Driving; Brain-Derived Neurotrophic Factor; CASP8 gene; CASP9 gene; Caspase; Cell Death; Cell Death Inhibition; Cell surface; Cells; Cessation of life; Complex; Development; Disease; Family; GDNF receptors; Grant; Growth; Growth Factor; Huntington Disease; In Vitro; Induction of Apoptosis; Inhibition of Apoptosis; Ligands; Link; Lysosomes; Mediating; Mediator; Membrane Microdomains; Molecular; Motor Neurons; Mus; Nerve Degeneration; Nerve Growth Factors; Nervous System; Nervous System Trauma; 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; Vertebral column; Withdrawal; axon guidance; deprivation; experimental study; gamma secretase; glial cell-line derived neurotrophic factor; in vivo; inhibitor; member; mouse genetics; nerve supply; neurogenesis; neurotrophic factor; proto-oncogene protein c-ret; receptor; release factor; small molecule inhibitor; somatosensory; transcriptional coactivator p75; Acceleration; Adult; Afferent Neurons; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Apoptotic; Automobile Driving; Brain-Derived Neurotrophic Factor; CASP8 gene; CASP9 gene; Caspase; Cell Death; Cell Death Inhibition; Cell surface; Cells; Cessation of life; Complex; Development; Disease; Family; GDNF receptors; Grant; Growth; Growth Factor; Huntington Disease; In Vitro; Induction of Apoptosis; Inhibition of Apoptosis; Ligands; Link; Lysosomes; Mediating; Mediator; Membrane Microdomains; Molecular; Motor Neurons; Mus; Nerve Degeneration; Nerve Growth Factors; Nervous System; Nervous System Trauma; 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; Vertebral column; Withdrawal; axon guidance; deprivation; experimental study; gamma secretase; glial cell-line derived neurotrophic factor; in vivo; inhibitor; member; mouse genetics; nerve supply; neurogenesis; neurotrophic factor; proto-oncogene protein c-ret; receptor; release factor; 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.

在整个发育中的神经系统中，都会产生非必要的神经元，或 在PNS中，程度 凋亡的凋亡受到有限的生存促进神经营养因素的控制 神经的靶标，以及凋亡引起的竞争因素，由“赢得神经元”分泌 已经成功地争夺了这些神经营养因素。神经胶质细胞系衍生的神经营养 因子（GDNF）家族配体（GFLS）是一个潜在生长因素的家族，支持生存 自主，体感和脊柱运动神经元。 GFL通过 一种常见的信号转移受体酪氨酸激酶，ret。在此赠款期间，我们发现 RET与TNF死亡受体家族的成员P75相互作用，P75增强了GDNF介导的RET激活和存活。当P75专门在感觉神经元中删除时， 在P14和成年之间损失了约20％，这些损失选择性地发生在RET+非肽性伤害感受器中。这些结果表明，p75是开发的 通过微调RET介导的营养支持，非肽性伤害感受器谱系。我们还发现 在PCD期间，上宫颈神经节（SCG）RET的交感神经元中限制为子集 迅速发生凋亡的神经元的退化神经元。促凋亡条件诱导 RET与p75的关联，从而增强了受调节的膜内蛋白水解（RIP）裂解 p75和下游凋亡作用的激活。删除RET+神经元中的p75和删除 RET，特别是在PCD期间，在体外和体内抑制凋亡。这些结果表明 RET在非人道上起作用可增强P75介导的细胞凋亡。基础的分子机制 p75增强RET信号传导的能力以及RET增强p75介导的死亡的能力不好 理解，并且是AIM 1的主题。我们最近还发现Semaphorin 3a（Sema3a）， 一个分泌的排斥轴突引导分子，诱导原发性SCG神经元的凋亡，并且 删除其接收器组件，Neuropilin-1（NPN-1）和Plexina3（PA3），大大降低了PCD 在SCG中。 SEMA3A通过需要caspase-8的外部途径诱导凋亡，而不是 NGF戒断触发的固有途径在需要caspase-9的交感神经元中。这 神经营养因子剥夺和死亡受体激活引起的凋亡的组合 开发的SCG提出了一个问题，即caspase-8和caspase-9有助于 PCD期间的凋亡以及哪些死亡受体正在推动这一过程。这些问题将是 目标2的主题。此处提出的实验将定义分子机制和 PCD中死亡受体途径（例如NPN-1/PA3和P75）所扮演的角色的大小。