Neurotrophin signals controlling development of the peripheral nervous system

控制周围神经系统发育的神经营养蛋白信号

• 批准号: 8769813
• 负责人: David D GINTY
• 金额: $ 5.3万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769813
• 关键词: Neurotrophin; signals; controlling; development; peripheral

DESCRIPTION (provided by applicant): The goal of this research is to elucidate principles and mechanisms that govern the assembly of neural circuits. The work focuses on the role of the target field, and in particular target-derived growth factors, in the control of neuronal survival and the establishment of synaptic connections between postganglionic sympathetic neurons and their presynaptic partners, and the differentiation of distinct classes of cutaneous sensory neurons. Proposed experiments address mechanisms and functions of the prototypical target-derived neurotrophic growth factor, nerve growth factor (NGF), and its receptor TrkA. NGF, expressed in targets of sympathetic and cutaneous sensory neurons, promotes target field innervation, survival, and synapse formation in the sympathetic nervous system through retrograde NFG/TrkA signaling. Retrograde NGF/TrkA signaling also controls target innervation, survival, and maturation of cutaneous sensory neurons. A main hypothesis to be tested is whether differential sorting and trafficking of TrkA-containing signaling endosomes account for the unique ability of NGF to support retrograde survival; the NGF family member NT3, an intermediate target- derived growth factor, cannot support retrograde survival. This is especially intriguing since both NGF and NT3 promote TrkA activation and TrkA-dependent axonal extension of sympathetic neurons. The work will assess the contribution of the actin cytoskeleton, and its modulation, during TrkA endosome formation, sorting, maturation, and trafficking. Proposed experiments will also address the exciting hypothesis that TrkA endosomes move retrogradely into cell bodies and then throughout the entire dendritic arbor where they instruct the formation of nascent postsynaptic specializations on dendrites. A third aim of the proposed work is to test the hypothesis that target-derived NGF signals retrogradely to promote expression of the transcription factor CBF2, which combines with the sensory neuron-subtype specific transcription factor Runx1 to instruct differentiation of non-peptidergic nociceptors. Thus, proposed work will provide insight into how the target field, and target-derived NGF, controls establishment and maintenance of PNS circuits. Since deficits of axonal transport and signaling and synaptic loss underlie forms of neurodegeneration, findings from the proposed work will be insightful not only for understanding normal development but also for maintenance of the nervous system under normal and disease states.

描述（由申请人提供）：本研究的目标是阐明控制神经回路组装的原理和机制。这项工作的重点是靶场，特别是靶标衍生的生长因子，在控制神经元存活和节后交感神经元与其突触前伙伴之间突触连接的建立，以及不同类别的皮肤感觉神经元的分化中的作用。拟议的实验探讨了原型靶源性神经营养生长因子、神经生长因子 (NGF) 及其受体 TrkA 的机制和功能。 NGF 在交感神经和皮肤感觉神经元的靶标中表达，通过逆行 NFG/TrkA 信号传导促进交感神经系统中的靶场神经支配、存活和突触形成。逆行 NGF/TrkA 信号还控制皮肤感觉神经元的目标神经支配、存活和成熟。需要测试的一个主要假设是含有 TrkA 的信号内体的差异分选和运输是否解释了 NGF 支持逆行生存的独特能力； NGF 家族成员 NT3 是一种中间靶标衍生的生长因子，不能支持逆行生存。这是特别有趣的，因为 NGF 和 NT3 都促进 TrkA 激活和交感神经元 TrkA 依赖性轴突延伸。这项工作将评估肌动蛋白细胞骨架及其调节在 TrkA 内体形成、分类、成熟和运输过程中的贡献。拟议的实验还将解决一个令人兴奋的假设，即 TrkA 内体逆行进入细胞体，然后遍及整个树突乔木，在那里它们指导树突上新生突触后特化的形成。该工作的第三个目的是检验以下假设：靶标衍生的 NGF 信号逆行促进转录因子 CBF2 的表达，CBF2 与感觉神经元亚型特异性转录因子 Runx1 结合，指导非肽能伤害感受器的分化。因此，拟议的工作将深入了解目标场和目标衍生的 NGF 如何控制 PNS 回路的建立和维护。由于轴突运输和信号传导的缺陷以及突触损失是神经退行性变的基础，因此拟议工作的发现不仅对于理解正常发育而且对于正常和疾病状态下神经系统的维持都具有深刻的洞察力。