Neurotrophin Signals Controlling Development of the Peripheral Nervous System

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 TrkAdependent 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 CBF, 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.