The function of the nervous system depends on precisely defined patterns of connectivity. Despite the importance of this process, the biological rules governing neural specificity are poorly understood. What are the molecular cues that result in the creation of synapses between specific sets of neurons? The complexity of the vertebrate nervous system coupled with the dearth of biochemical information about synaptic choice have hindered efforts to answer this question in mammals. Our strategy to circumvent these problems is, first, to address this question in a simple, well-defined nervous system and, second, to employ a genetic approach which does not require prior assumptions about the molecular mechanism of neural specificity.
In the nematode, Caenorhabditis elegans, the nervous system is composed of exactly 302 neurons. Every contact between these cells has been catalogued to construct a complete wiring diagram. With this detailed information in hand, it is possible to correlate mutations that produce abnormal or "uncoordinated" movement with specific changes in the structure of the nervous system. A mutation in one of these genes, the transcription factor unc-4, alters the pattern of synaptic input to one class of motor neurons in the ventral nerve cord and results in a strong movement defect. We hypothesize that unc-4 defines a specific motor neuron trait that is recognized by potential presynaptic partners and that these traits are encoded by downstream genes that unc-4 regulates. A major goal in the Miller lab is to identify these unc-4 target genes. Recently, we implemented a pioneering cell-specific profiling strategy to reveal one of these downstream genes, the transcription factor, CEH-12/HB9 (Von Stetina et al., 2007). Expression of CEH-12/HB9 in the vertebrate spinal cord suggests that the role of this pathway may be conserved in more complex motor circuits. Our long term aim is to work out the molecular and cellular mechanism of neural specificity in this simple model system and then to extend our findings to complex vertebrate nervous systems which could not otherwise be dissected by this genetic approach. Other projects in the Miller lab include mechanisms of neurodegeneration, synaptic plasticity, sensory neuron morphogenesis and a genome-wide effort to define the C. elegans transcriptome (modENCODE.org).