A fundamental problem in developmental neurobiology is to understand how nerve cells (neurons) choose their identities. One critical decision a neuron makes during development is its choice of neurotransmitter — that is, the chemical substance it uses to relay information to another neuron. To use a particular neurotransmitter, a neuron must express a unique set of proteins by activating specific genes. We are studying the control of this process in a simple organism, the free-living nematode, Caenorhabditis elegans, which has only about 1000 cells, a third of which are neurons. C. elegans is one of the premier model organisms in biology today. This free-living soil nematode (roundworm) was the first multicellular organism for which scientists obtained a complete genomic DNA sequence. This tiny worm shares many common developmental mechanisms with higher animals.
We are interested in how genes are regulated in serotonergic and dopaminergic neurons, and the behaviors controlled by these neurons. We also study the evolution of behavior and neuronal patterning in the nervous system. We have begun to examine the patterning of serotonergic neurons in a variety of related nematodes, and to examine the behaviors regulated by serotonin in those species, such as the experience-dependent regulation of locomotion, egg-laying and male mating.
The enzymes catalyzing the first steps in serotonin and dopamine synthesis (Tryptophan hydroxylase and Tyrosine hydroxylase, respectively) both require a cofactor called biopterin. They share this feature with a related enzyme called phenylalanine hydroxylase (PAH) which converts the amino acid phenylalanine to tyrosine, and a distinct lipid metabolic enzyme called alkyl glycerol monooxygenase (AGMO). In C. elegans, both PAH and AGMO are expressed in skin cells and seems to be necessary for proper cuticle construction. Biopterin is synthesized in the cells that need it; therefore serotonergic and dopaminergic neurons and skin cells also express biopterin synthesis (and related) genes. Because of these connections, we are studying the function of AGMO, PAH and biopterin in both the skin and neurons. We have found that dysfunction of AGMO in the skin causes altered sensitivity to bacterial pathogens.