UC San Diego

The central nervous system (CNS) is made up of trillions of connections between specific sets of highly specialized neurons. How each individual neuron finds and connects to the correct synaptic partner remains an important and unresolved issue in neuroscience. Using the mouse visual system as a model I probed the cellular and molecular mechanisms that govern one of the key steps leading to CNS development: axon target matching. Axon target matching is the process by which axons to find and innervate their correct target nuclei in the brain. I focused on eye-to-brain connections made by retinal ganglion cells (RGCs). First, I discovered that RGC birthdate correlates with the timing of axon out growth from the eye to the brain and that the timing of axon arrival predicts the mode of axon target matching. The earlier an RGC axon innervates the brain, the more targets it innervates and ultimately the more axonal refinement must take place before it reaches the final wiring pattern. Conversely, the later an RGC axon innervates the brain the more likely it will project to only the correct targets and undergo minimal refinement. Second, I discovered that specific adhesion molecules expressed by RGC axons and/or the cells in their target nuclei are required for correct axon target matching. These include cadherin-6, contactin-4 and amyloid precursor protein. I found that a loss of a single adhesion molecule and thereby the loss of connections made by a single functionally-specialized category of RGCs to the brain, results in system-wide defects in specific visually-driven behaviors.¬ My results shed light on how sensory neurons in the mammalian visual system rely on timing of cell birth and axon outgrowth, along with specific cell adhesion molecules to form highly specialized long-range connections required for correct visually-driven perception and behavior. These results speak to possible general mechanisms of neural development in the CNS.