The molecular basis of neuronal circuit formation

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The development of the nervous system can be subdivided broadly into two phases. First, the various types of nerve cells are specified. Second, nerve cells migrate to their proper locations, send out thin processes (axons and dendrites) and connect to target cells by forming synaptic connections. My research group is studying the molecular mechanism underlying the second phase, specifically axonal pathfinding leading to the formation of neuronal circuits. The overall goal of my research program is to dissect and understand the fundamental molecular mechanisms underlying neuronal circuit formation. To this end the proposed research focuses on the identification of the missing molecular players involved in axonal pathfinding. In objective 1 we will characterize several novel axon guidance receptors that we recently identified and continue to screen a list of candidate genes for additional receptors. One of the receptors is a putative neuropeptide receptor. This is (indirect) evidence that neuropeptides act during axonal navigation as potential cues for navigating axons. Thus we plan to characterize the role of neuropeptides in axon pathfinding in more detail. In objectives 2 and 3 we will address the unresolved question of how axons are positioned properly within an axon bundle. This is essential for correct synapse formation and neuronal circuit formation. This question could not be addressed effectively in the past, because of the need to use electron microscopic studies to detect positioning defects at the single axon level. The development of super-resolution microscopes allows us now to develop and use light-microscopic markers to identify the molecules responsible for axon positioning. ***Taken together these experiments will identify a substantial number of novel putative axon guidance receptors required to establish neuronal circuits. Since all known axon guidance systems are evolutionarily conserved from invertebrates to vertebrates, our studies will provide substantial insights into the way neuronal circuits are formed in general and provide researchers working with vertebrate model organisms important insights into the molecular basis of vertebrate brain development.