Neurotrophin signals controlling development of the peripheral nervous system

描述（由申请人提供）：本研究的目的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区，特别是靶源性生长因子，在神经元存活的控制和神经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。拟建的实验研究了典型的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表达于交感和皮肤感觉神经元的靶点，通过逆行的NFG/TrkA信号传导促进交感神经系统靶场神经支配、存活和突触形成。逆行的NGF/TrkA信号还控制着靶神经的支配、皮肤感觉神经元的存活和成熟。需要验证的一个主要假设是，含有trka的信号内体的不同分类和运输是否解释了NGF支持逆行生存的独特能力；NGF家族成员NT3，一种中间靶源性生长因子，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TrkA依赖的交感神经元轴突延伸。这项工作将评估肌动蛋白细胞骨架及其在TrkA内体形成、分选、成熟和运输过程中的调节作用。拟议的实验也将解决令人兴奋的假设，即TrkA内体逆行进入细胞体，然后穿过整个树突乔木，在那里它们指导树突上新生的突触后特化的形成。本研究的第三个目的是验证目标来源的NGF信号逆行促进转录因子CBF2的表达的假设，CBF2与感觉神经元亚型特异性转录因子Runx1结合，指导非肽能性伤害感受器的分化。因此，提出的工作将深入了解目标场和目标衍生的NGF如何控制PNS电路的建立和维护。由于轴突运输、信号传导和突触丧失的缺陷是神经退行性疾病的基础，因此这项工作的发现将不仅对理解正常发育，而且对正常和疾病状态下神经系统的维持具有深刻的见解。

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.