The development of the central nervous system involves two series of patterning events: the generation of discrete classes of neurons in a precise spatial array, followed by the growth of axons to establish an appropriate network of synaptic connections. We are using molecular and embryological approaches to understand the mechanisms underlying these events in vertebrates.
Our work currently focuses on the mechanisms by which the axons of one set of spinal neurons, commissuralneurons, are guided to their targets during development. An intermediate targets of these axons, the floor plate, secretes a diffusible chemoattractant for these axons. We have recently purified a candidate for this attractant, which we have named netrin 1, and in the process have identified a related protein, netrin 2. We have found that netrin 1 can also function as a chemorepellent for axons that grow away from the floor plate, showing that netrin 1 is a bifunctional guidance cue that may serve to attract some axons to the floor plate while steering others away. Remarkably, the netrins are vertebrate homologues of the UNC 6 protein of C. elegans, which is also hypothesized to function as both an attractant and a repellent in the nematode. Our current aims are to elucidate the role of the netrins in axon guidance through manipulation of their function in vivo, and to determine how axons detect gradients of the netrins and reorient growth in response to these gradients. We have also initiated studies to identify other attractants and repellents.
Another major interest is the role of inductive interactions in the patterning of cell types in neural and mesodermal tissue at earlier stages of development. In particular, we have studied the mechanisms responsible for the patterning of the somitic mesoderm into dermomyotome (precursor of muscle and dermis) and sclerotome (precursor of cartilage and bone). We have characterized several of the tissue interactions and one of the signaling molecules (Sonic hedgehog) that appear to be responsible for this patterning.