The nervous system is composed of many neurons connected into complex circuits. These circuits are connected largely through carefully choreographed processes of axon guidance. Currently, a major focus in the lab is the molecular and cellular mechanisms conveying directionality and specificity in axon pathfinding and target selection. Axonal connections in the nervous system are highly organized, often patterned along major axes. The nature of anterior-posterior guidance cues has remained elusive until recent years. We found that Wnt family proteins direct a class of ascending sensory axons to project along the spinal cord towards the brain and the descending growth of corticospinal tract axons in the opposite direction. We are examining whether these Wnts are involved in the anterior-posterior pathfinding of other classes of axons.

How intracellular signaling pathways lead to the turning of growth cones in response to concentration gradients of guidance cues remain largely unknown. Even less clear is how growth cones change responsiveness at intermediate targets. We are using Wnt signaling as a tool to understand how intracellular pathways are activated and how they work collaboratively to orchestrate coordinated changes within a cell.

One common method connecting the nervous system is through the use of topographic mapping, whereby positional orders of neurons are smoothly and continuously mapped to their targets. Classical studies and computational modeling have predicted that at least two counterbalancing forces are required to make a map. We found that Wnt3 is a force that can guide retinal ganglion cell axons to terminate laterally and counterbalances the medially directing force of ephrinB1. We are currently testing the role of Wnts in mediating topographic connections in different brain areas and whether the two-molecular-gradients model holds true in the formation of other maps.