Neural Development and Behavior

We have identified and characterized genes responsible for axonal outgrowth as well as for other aspects of neuronal differentiation. We are analyzing both how the nervous system controls behavior and how genes specify the functioning of a neuromuscular system. We have used a laser microbeam, pharmacology and mutations to identify which neurons control specific behaviors. We have analyzed how the environment and experience modulate the locomotory rate of C. elegans and have discovered that the animal’s serotonergic nervous system plays a central role in its response to its experience. These studies have allowed us to identify and analyze an ionotropic ligand-gated serotonin receptor and a serotonin-reuptake transporter similar to the target of human antidepressants (e.g., Prozac). We have also identified genes that control a two-pore potassium channel complex involved in muscle contraction.

The C. elegans nervous system consists of only 302 neurons and 56 glial-like cells. The 302 neurons are of 118 distinct classes, based upon morphology, neurotransmitter content and connectivity. The complete reconstruction of the C. elegans nervous system from serial section electron micrographs defined a wiring diagram with about 5000 chemical synapses, 2000 neuromuscular junctions and 600 gap junctions. The neurotransmitters used by C. elegans are generally the same as those used by other animals: acetylcholine is the major excitatory neurotransmitter, and GABA is the major inhibitory neurotransmitter; glutamate, serotonin, dopamine, octopamine (an invertebrate counterpart of norepinephrine) and various neuropeptides are also active. Because the complete cell lineage of C. elegans has been described, we know the developmental origin of every neuron and the precise lineal relationships among neurons of different types. We have identified and characterized many genes responsible for many aspects of nervous system development, including the acquisition of neuronal identity, neuronal cell migration, axonal outgrowth and neurotransmitter expression. Among the genes we found to control axonal outgrowth are genes that encode components of a DCC/netrin pathway, modifiers of the actin cytoskeleton, and several novel proteins. We have recently focused on a subset of the genes involved in axonal outgrowth that also function to effect other cell-shape changes, including changes in cell-corpse engulfment and cell migration. These genes encode members of the Rac/Rho GTPase family and regulators of the activities of these G proteins.