I. Description: Substantial evidence suggests that activity plays a crucial instructive role in shaping the structure and connectivity of the central nervous system, but the molecular mechanisms that translate developmental activity patterns into lasting structural changes in the brain remain open mysteries. Neurotrophins have long been implicated as candidate signaling molecules that potentially mediate activity- dependent development, but their in vivo roles have been difficult to predict based on conventional genetic approaches or culture studies. By using a novel genetic mosaic approach to generate small groups of labeled homozygous mutant cells in intact animals, this proposal will dissect the role of activity and neurotrophin signaling in brain development in vivo, with single-cell resolution. Specifically, the proposal will combine inducible genetic strategies and genetic mosaic analysis to test the function of neurotrophin receptors p75, TrkB, and TrkC in development and refinement of central somatosensory circuitry. The somatosensory system relies on activity for proper structural maturation of both axons and dendrites, and thus represents an excellent opportunity to test key hypotheses in neurotrophin signaling, activity-dependent development, and neural circuit formation. As p75 and Trk receptor dysfunction contributes to neurological disorders including Alzheimer's disease and schizophrenia, potential results will also have broad implications for our understanding of neural circuit maintenance and repair, as well as therapeutic approaches to neurodevelopmental and neurodegenerative diseases.
Project Summary / Abstract II. Relevance: This proposal will study the molecular mechanisms by which activity influences nerve cell structure during brain development. Proper development of cell shape and connectivity in the central nervous system is critical for perception and cognition. Accordingly, studies in nerve cell morphogenesis will considerably aid our understanding of how the brain wires itself during development, how our early experiences can generate long-lasting changes in our brains, what happens when nerve cells are injured by neurodegenerative disease or trauma, and how we can repair nervous system damage.
|Joo, William; Hippenmeyer, Simon; Luo, Liqun (2014) Neurodevelopment. Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling. Science 346:626-9|
|Joo, William J; Sweeney, Lora B; Liang, Liang et al. (2013) Linking cell fate, trajectory choice, and target selection: genetic analysis of Sema-2b in olfactory axon targeting. Neuron 78:673-86|