The Miller lab focuses on the genetic mechanisms of neural development, in particular on how genetic programs define synaptic specificity in the nervous system. Animal movement depends on the highly specialized and stereotypic links between motor neurons and muscles. The lab utilizes the nematode, C. elegans, with its simple, well-defined nervous system and powerful genetics, to identify key molecules regulating motor neuron differentiation, patterned interconnection, and function. Lab members have shown that the UNC-4 homeodomain transcription factor governs the pattern of synaptic inputs to the correct motor neurons in the nerve cord.
One major focus of the Miller lab's research is to identify other genes in the Unc-4 pathway and reveal their cellular and molecular mechanism of action. Towards this goal, they have developed powerful microarray-based methods for gene expression profiling of specific normal and mutant cells, and used them to identify UNC-4 target genes. Lab members are also employing similar strategies to define downstream players in other developmental events that are under strict transcriptional control, including the pathways that regulate synaptic remodeling and sensory neuron morphogenesis. Other applications include a large-scale project to correlate neuron-specific gene expression with the wiring diagram of the nematode nervous system, and a “modENCODE”-funded effort to identify all active genes in the C. elegans genome as a model for deciphering the inter-regulation of human gene expression. Lastly, lab members are exploiting the genetic ease of C. elegans to reveal key players in the mechanism of neuron-specific degeneration.