Neurotrophin signals controlling development of the peripheral nervous system

描述(申请人提供)：这项研究的目标是阐明支配神经回路组装的原理和机制。这项工作着重于靶区，特别是靶源性生长因子在控制神经元存活、节后交感神经元与其突触前伙伴之间建立突触连接以及不同类别皮肤感觉神经元的分化中的作用。拟议的实验解决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在交感和皮肤感觉神经元靶点表达，通过逆行NFG/TrkA信号通路促进交感神经系统靶区神经支配、存活和突触形成。逆行的NGF/TrkA信号也控制皮肤感觉神经元的靶神经支配、存活和成熟。有待检验的一个主要假设是，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是一种中间靶源生长因子，不能支持逆行生存。这是特别有趣的，因为NGF和NT3都促进了TrkA的激活和TrkA依赖的交感神经元的轴突延伸。这项工作将评估肌动蛋白细胞骨架在TrkA内体形成、分选、成熟和运输过程中的作用及其调节。拟议的实验还将解决令人兴奋的假设，即TrkA内小体退行性进入细胞体，然后遍及整个树突，在那里它们指导树突上新生的突触后特化的形成。这项拟议工作的第三个目的是检验这样一种假设，即靶向衍生的NGF信号逆行地促进转录因子CBF2的表达，CBF2与感觉神经元亚型特异性转录因子RUNX1结合，指导非肽能伤害性受体的分化。因此，拟议的工作将深入了解靶场和靶源NGF如何控制PNS电路的建立和维护。由于轴突运输和信号的缺陷以及突触丢失是神经变性的基础，因此这项拟议工作的发现不仅对于理解正常发育，而且对于维持神经系统在正常和疾病状态下的发育都是有洞察力的。

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.