Molecular genetics of neural specificity in Caenorhabditis elegans.
The human brain embodies the most complex and functionally remarkable tissue in biology. These attributes are defined by elaborate, highly connected networks in which myriad types of neurons are linked together in circuits with discrete physiological roles. I am interested in fundamental mechanisms that drive the creation and maintenance of this intricate structure. To obviate the need to study the brain directly, we are using the model organism, C. elegans, to reveal the underlying programs that specify neural architecture. With its simple, well-defined nervous system and facile genetics, C. elegans, is especially well-suited to this approach. For example, the phenomenon of synaptic specificity is readily evident in the wiring diagram of the C. elegans nervous system which catalogs synaptic partners for all 302 neurons in the circuit. We have exploited this resource to identify genetic mutants that alter connectivity and thus define pathways that are normally required for directing the creation of synapses between specific neurons. The execution of these developmental programs depends on expression of unique combinations of genes in different types of neurons. With the goal of identifying these genetic signatures, the Miller lab has pioneered the development of robust methods for generating neuron-specific gene expression profiles. Reverse genetic strategies (e.g., RNAi) are then employed to test candidate genes from these lists for key roles in circuit architecture. Perturbations are readily detected in this small, transparent organism with high-resolution light microscopy of neurons and synapses marked with fluorescent proteins (e.g., GFP). In addition to uncovering mechanisms that direct synaptic specificity, the Miller lab has also used these methods to address other fundamental processes in neural development including synaptic plasticity, dendrite morphogenesis and nerve regeneration. These studies are expected to reveal genetic networks with similar roles in human brain development and thus can lead to a deeper understanding of mechanisms that protect the brain from disease and repair damage arising from injury.