News and Publications

Molecular Mechanisms of Sensory Neuron Specification and Function

A. Patapoutian, T. Earley, A. Moqrich, G. Story

Sensory neurons of the dorsal root ganglia (DRG) are highly specialized cell types that convey sensations of pain, temperature, light touch, and limb position. Our long-term objective is to understand the molecular pathways that underlie the development and function of these neurons. Neurotrophins and their trk receptors are expressed in and are required for survival of distinct DRG subpopulations; for example, NGF/trkA is specifically required for the survival of pain-sensing neurons.

Furthermore, our recent findings suggest that neurotrophins play an instructive role during DRG neuronal development. We hypothesize that the expression of a specific trk is sufficient to impose subtype specificity on these neurons. We are testing this hypothesis by replacing one trk receptor with another in the mouse genome. To extend our knowledge of the molecular pathways beyond the neurotrophins, we must identify other genes involved in both developmental and functional aspects of DRG neurons.

Because mice that lack genes for trk receptors also lack specific DRG subtypes, we are analyzing these mice by using expression array methods to identify genes uniquely expressed in distinct DRG classes. In situ hybridizations confirm that many of the genes we identified are specifically expressed in DRG subtypes. We are currently assessing the function of these genes in experiments with neuronal cell lines and transgenic mice.

In addition, we are using a candidate approach to identify molecules that play important roles in the actual detection of various mechanical and thermal stimuli relevant to pain and other DRG neurons. One molecule involved in such detection is vanilloid receptor 1, a heat-gated channel that is expressed in a subset of pain neurons. We cloned novel vanilloid receptor 1--related proteins expressed in sensory neurons and are characterizing their function.

Finally, in a collaborative effort with the Genomics Institute of the Novartis Research Foundation, San Diego, California, we are conducting a large-scale N-ethyl-N-nitrosourea screening for behavioral phenotypes in mice. We are screening for mutants with altered sensitivity to pain, temperature, and proprioception (sense of position). We have early indications that such mutants can indeed be identified.

PUBLICATIONS

Patapoutian, A., Reichardt, L.F. Trk receptors: Mediators of neurotrophin action. Curr. Opin. Neurobiol. 11:272, 2001.

Patapoutian Website