Neurotrophins regulate critical cell fate decisions, by modulating neuronal survival, differentiation, and morphology during development. Neurotrophins are initially synthesized as a precursor, or proneurotrophin, which can be cleaved to a mature form that mediates survival and differentiation actions via the Trk receptor tyrosine kinases. However, proneurotrophins, including proBDNF, exert independent cell fate decisions by activating the p75 receptor and sortilin, to mediate cell death. In preliminary studies, we have identified two new components of the proneurotrophin receptor complex, and provide evidence that through the utilization of different co-receptors, that proneurotrophins can initiate distinctive signaling pathways, to induce neuronal apoptosis, or to acutely induce growth cone pruning, resulting in decreased dendritic complexity in vivo. During the prior funding cycle, we have also identified new signaling partners downstream of p75, real time imaging techniques to quantitatively measure acute remodeling of neuronal processes, and a new conditional knock-in mouse to evaluate the effects of proBDNF at the biochemical level, in neuronal cultures and in in vivo paradigms. Here we propose three interrelated aims to molecularly dissect the mechanisms by which proneurotrophins regulate distinct cellular fates of apoptosis, or acute cytoskeletal remodeling. First, we will examine the receptors complexes that bind to proBDNF and proNGF, and determine how the choice of receptor subunit ultimately dictates biological responses. Specifically, we will identify how p75 differentially partners with distinct sortilin family members and with a related receptor component, NRH2. We will then test how these receptor complexes engage different signaling pathways to promote apoptosis or acute morphological responses that result in growth cone collapse. Second, we will dissect two signaling pathways downstream of p75, mediated by PKC activation or GTPase inactivation, which initiate pruning responses to proneurotrophins, using real-time quantitation of growth cone movement. Lastly, we will utilize our newly generated inducible proBDNF knock-in mouse to identify the critical "windows of vulnerability" in which proBDNF mediates apoptotic or remodeling outcomes in the developing hippocampus, and in peripheral sympathetic neurons. By regulating proBDNF expression in early development, or in the adult, we will directly test whether the effects of proBDNF are limited to perinatal ages, to sculpt neuronal morphology and to regulate the generation of distinct subpopulations of neurons, or are utilized throughout adulthood to continue to prune connectivity and modulate synaptic transmission.
Neurotrophins, including brain derived neurotrophic factor (BDNF) have pleiotropic effects on neural development and synaptic plasticity that underlie circuit formation and cognitive function;even modest changes in BDNF levels lead to behavioral changes in humans or mouse models. BDNF is first synthesized as a precursor, proBDNF, that induces cell death, or pruning of neuronal processes, actions distinct from the survival effects of mature BDNF. Here, we use technical advances of new receptor components and signaling pathways activated by proBDNF, and a mouse model to dissect proBDNF actions in the developing brain. These studies permit us to determine how proBDNF regulates neuronal cell fate, and the regressive events of naturally occurring neuronal death and pruning of dendrites, to establish appropriate neuronal circuitry.
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