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: 9886974
• 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/9886974
• 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.

在整个发育中的神经系统中，产生了多余的非必需神经元，或者