Neurotrophin signals controlling development of the peripheral nervous system

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。这项工作的重点是作用的目标领域，特别是目标衍生的生长因子，在控制神经元的生存和建立突触连接的节后交感神经元和他们的突触前合作伙伴，和分化的不同类别的皮肤感觉神经元。提出的实验解决机制和功能的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。在交感神经和皮肤感觉神经元的靶中表达的NGF通过逆行NFG/TrkA信号传导促进交感神经系统中的靶区域神经支配、存活和突触形成。逆行性NGF/TrkA信号传导还控制皮肤感觉神经元的靶神经支配、存活和成熟。待检验的主要假设是含TrkA的信号传导内体的差异分选和运输是否解释了NGF支持逆行存活的独特能力; NGF家族成员NT 3（一种中间靶源性生长因子）不能支持逆行存活。这是特别有趣的，因为NGF和NT 3都促进交感神经元的TrkA激活和TrkA依赖性轴突延伸。这项工作将评估肌动蛋白细胞骨架的贡献，及其调制，在TrkA内体形成，分选，成熟和贩运。拟议的实验还将解决令人兴奋的假设，TrkA内体逆行进入细胞体，然后在整个树突乔木，在那里他们指示新生突触后树突专业化的形成。所提出的工作的第三个目的是测试的假设，靶源性神经生长因子信号逆行促进转录因子CBF 2的表达，结合感觉神经元亚型特异性转录因子Runx 1，以指导非肽能伤害感受器的分化。因此，拟议的工作将提供深入了解如何的目标领域，和目标衍生的神经生长因子，控制建立和维护的PNS电路。由于轴突运输和信号传导的缺陷以及突触丢失是神经变性形式的基础，因此拟议工作的发现不仅对于理解正常发育而且对于在正常和疾病状态下维持神经系统都具有深刻的意义。

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.