UC San Diego

The ability of the mammalian central nervous system to interpret the environment accurately, integrate information efficiently, and generate appropriate responses depends on the precise wiring and organization of billions of neurons into functional networks. The establishment of neural circuits to enable the eventual flow of sensory information requires that axons navigate across vast (on a cellular scale) distances. For somatosensory neurons, guidance takes place during development when axons must grow to the brain via a series of intermediate targets, each step of which involves the detection and response to numerous extracellular cues. Therefore, to develop a comprehensive understanding of how neurons form appropriate connections requires that axonal responses to these molecular guidance cues be clearly defined. This dissertation presents studies of axon guidance in a model cellular system, the somatosensory commissural neurons of the spinal cord. I have characterized the role of Wnt-Frizzled signaling in these neurons, and found that the non-canonical Wnt-Fzd signaling, known as the Planar Cell Polarity (PCP) pathway, is fundamental to commissural axon guidance. Further, by analysis of animal models of PCP dysfunction, Celsr3 null and Vangl2 mutant mice, I show that PCP is required for anterior guidance of commissural axons toward the brain. Equally important, I describe the mechanism by which the PCP pathway mediates axon growth decisions through the use of primary spinal neuron and eukaryotic cell cultures and biochemical techniques. I present evidence to show that modifications of PCP surface receptors, Fzd3 and Vangl2, at the cell membrane are critical to PCP signaling and constitute a spatio-temporal response to Wnt molecules secreted from the ventral spinal cord. Together, these data reveal a novel role for the PCP pathway in axon guidance. It is hoped that the results of these studies will provide a more general model for the role of membrane receptor modifications in the establishment of neuronal circuitry