In contrast to our growing understanding of spinal cord development, the factors controlling specification and patterning of peripheral sensory neurons are poorly understood. Recent work from our laboratory provides evidence that sensory neurons have unique phenotypes prior to their extension into the periphery. Using a new method to enrich for populations of early sensory neurons with different developmental fates, we have shown that sensory neuron subtypes (e.g. cutaneous versus proprioceptive) have unique patterns of gene expression and differing abilities to interact with matrix proteins shortly after they are born. This work provides evidence for the early specification of sensory neurons, independent of target interactions, and thereby limits the developmental window over which sensory neuron specification can occur. In addition, our results have, for the first time, provided valuable prospective markers for sensory neuron subtypes that will greatly enhance future studies of sensory neuron development. We will build on our recent findings in three ways.
In Aim 1, we will exploit the new method we have developed to screen gene expression profiles of different sensory subtypes. We will focus on axon guidance molecules known to direct the pathfinding of central neurons. This work will both expand our available markers for further study of sensory development and provide useful information regarding sensory pathfinding, a question about which very little is currently known.
In Aim 2, we will pursue our observation that sensory specification must occur early in the development. Preliminary evidence presented in this proposal suggests that molecules involved in the patterning and specification of central neurons also influence the developing dorsal root ganglia. We will examine gain and loss of function experimental conditions to determine whether specific patterning molecules are necessary and sufficient to alter sensory neuron proliferation, death and patterning.
In Aim 3, we will pursue our initial findings that members of the netrin-1 signaling pathway are differentially expressed between different prospective classes of sensory neurons to ask what role netrin-1 signaling may play in the development of central and peripheral sensory projections. We will experimentally test three potential roles for netrin-1 in sensory development; the regulation of initial proprioceptive outgrowth, control of the timing for proprioceptive central projections and the establishment of dorsal projections of motor and sensory neurons in the dorsal ramus.
