CNS damage caused by abnormal development, injury or disease profoundly impacts quality of life. For example, spinal cord injuries are relatively common, but strategies to repair or regenerate damaged sites remain elusive. To develop more effective treatments it is essential that we understand the molecular mechanisms that produce functional spinal cord circuits. In addition, if we are to understand the genetic basis of neuro-developmental and behavioral disorders we need to understand how specific genes regulate the development of neuronal circuitry and hence enable particular behavioral repertoires. A particularly tractable model system for this research is spinal cord circuitry. This is partly because the development and functions of this circuitry can be studied in simpler vertebrates such as zebrafish and partly because the spinal cord is a much simpler structure than the brain. Specification of distinct types of neurons with particular functional properties is a crucial step in circuit formation. Interneurons constitute most of the neurons in the CNS and they function in almost all neuronal circuits. However, there are significant gaps in our knowledge of how spinal interneurons with specific functional characteristics develop and form appropriate neuronal circuitry. All of the evidence so far, suggests that the properties of distinct interneurons are determined by the transcription factors that these cells express as they stop dividing and start to differentiate. However, in many cases, it is still unclear which transcription factors specify particular properties, at least partly because we do not yet know the full complement of transcription factors expressed by any population of spinal interneuron.
To address these critical gaps in knowledge we have expression-profiled different spinal interneurons using transgenic zebrafish lines that specifically label these cells. Using these data, we have identified transcription factors that are candidates for specifying particular interneuron properties and we are currently testing the functions of these using mutations. Notably we have already identified several families of transcription factors that are required to specify and/or maintain the neurotransmitter properties of particular spinal interneurons. For example, we have shown that Pax2 & Pax8 are required for the inhibitory fates of many distinct spinal neurons and Evx1 & Evx2 are required for the excitatory fates of V0v neurons. We have also identified additional transcription factors that are required either for the inhibitory fates of distinct ventral neurons or the excitatory fates of specific dorsal neurons or to maintain the glutamatergic fates of some excitatory neurons.