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2. Role of the Prdm transcription factors in spinal cord patterning and neurogenesis

In vertebrates, locomotion is a routine but highly complex motor behavior that requires delicate control and coordination of the movements of the limbs. Although the planning of movements is elaborated in cortical and subcortical regions of the encephalon, rhythmic limb movements involved in locomotion are driven, coordinated and finely regulated by local neuronal circuits located in the ventral part of the spinal cord. The establishment of those neuronal circuits depends critically on the generation of distinct neuronal cell types at proper times and positions during embryogenesis. Understanding the mechanisms that control during normal development the generation of the distinct classes of neurones in the ventral spinal cord in spatially and temporally coordinated programmes, as well as their integration into functional locomotor network is a key step to uncover the mechanisms of neurological diseases of the locomotor system.

Current projects in this area include the study of several members of the Prdm family of genes encoding transcriptional regulators containing a N-terminal SET domain functioning in chromating mediated transcriptional repression, followed by a variable number of zinc finger repeats. Several studies, including our recent work on one family member, Evi-1/prdm3, have shown that some of these genes are essential for embryonic development. We found that several members of the prdm family are expressed in the developing Xenopus CNS in spatially restricted domains of neural progenitors in the developing spinal cord and that their expression profile is conserved in chick and mouse embryos. Among them, prdm12 is of high interest given its expression domain restricted in the spinal cord to the progenitors of the V1 interneurons (INs), suggesting a function for this gene in their development.

To approach the function of the prdm12 gene in spinal cord neurogenesis, we performed gain and loss of function experiments in the developing frog embryo and obtained evidence that it is a critical determinant of V1 IN progenitor cell identity. We are currently trying to further understand the role of Prdm12 in spinal cord neurogenesis by overexpresssing it by electroporation in the chick spinal cord and by generating mice that display loss of function of prdm12. We are also trying to identify the DNA sequences to which Prmd12 binds by in vitro selex experiments and its in vivo targets by chromatin immunoprecipitation experiments. The role of several other members of the Prdm family is also approached by gain and loss of function experiments in the frog embryo.