Long distance regressive signaling underlies sculpting of the nervous system during development. - PROJECT SUMMARY Neurodevelopmental events occurring after axons innervate their targets can be categorized as either progressive (e.g., cell survival, axon stabilization, promotion of synapse formation) or regressive (e.g., cell death, axon degeneration, synapse restriction). While the molecular and cellular basis of long-distance progressive signaling is relatively well-characterized, the understanding of long-distance regressive signaling remains limited. Many target-derived regressive cues, such as trophic factor deprivation (TFD), repulsive axon guidance cues, neurotrophin and pro-neurotrophin binding, converge on the p75 neurotrophin receptor (p75NTR). Studying this single receptor offers an opportunity to explore the molecular basis of various long-distance regressive signaling events. This research holds significance for understanding neurodevelopmental disorders such as autism and schizophrenia, as well as a wide range of neurodegenerative conditions, including ALS, Huntington's, Parkinson's, and Alzheimer's disease. The mechanism regulating the transmission of target-derived regressive cues back to the cell body is an emerging area of study. Currently, there is a significant gap in our knowledge regarding how p75NTR transitions from the plasma membrane to endosomal signaling and from the axon to the cell soma. The general concept motivating this application is that p75NTR must be internalized, cleaved, and palmitoylated to traffic and convey long-distance degenerative signals. However, it is unclear whether all regressive ligands and trophic factor deprivation relying on p75NTR require each of these events or how progressive signals interfere with these processes. The rationale for this proposal is based on our preliminary findings that: 1) p75NTR is cleaved and becomes endosomally associated after distal axon treatment with a regressive cue, and 2) palmitoylation of p75NTR is required for endosomal localization and retrograde death signaling. The exact regulatory mechanism behind this remains an open question. In Aim 1, we will characterize the features of p75NTR long-distance regressive signaling during apoptosis, axon degeneration and synapse restriction, as well as investigate how crosstalk from NGF-TrkA progressive signaling influences these processes. In Aim 2, we will examine the role of p75NTR palmitoylation in regressive signaling and assess the physiological effects of palmitoylation on regressive developmental events in vivo. Our overarching goal is to unravel the role of long-distance regressive signaling in nervous system development and its regulation.
