| Summary: | The establishment of correct neural circuitry in the nervous system requires the interplay, integration, and coordination of a diverse set of cells and signals during development and in the adult. Two important events are the regulated initiation and growth of dendrites that receive and process synaptic information, and the establishment and maintenance of appropriate neural connectivity. The goals of this study are to identify the molecular mechanisms underlying dendrite growth and initiation, and to understand how neural connectivity is maintained in the adult nervous system.
I first identified a novel intracellular signal transduction pathway involving two kinases important in regulating dendrite development. I showed that the ILK-GSK3beta pathway is required for dendrite growth and initiation in both peripheral and central nervous system neurons.
I then asked how neural connectivity is maintained in the adult nervous system by examining the role of myelin in the intact nervous system. My results indicate that when myelin contacts aberrantly growing axons, it activates on those axons the p75 neurotrophin receptor (p75NTR), which in turn causes the local degeneration of those axons. I further identified the signal transduction pathway required for axon degeneration consisting of p75NTR and intracellular signaling proteins activated by this receptor, Rho-GDI, Rho, and caspase 6. This data establishes p75NTR as an important regulator of neural connectivity and identifies for the first time a degeneration-inducing signal transduction pathway activated by myelin. It also provides an explanation for why myelin inhibits regeneration of injured central nervous system axons.
Taken together, I identified a new signaling pathway important for regulating dendrite initiation and growth, and a novel role for myelin in maintaining neural connectivity. Both of these findings contribute to our knowledge of how such connectivity is established during development and maintained in the adult nervous system.
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