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3. Role of the doublesex/mab3 related-5 (DMRT5) transcription factor in brain development

The cerebral cortex which derives from the embryonic dorsal telencephalon is the seat of the highest cognitive functions in mammals. It can be subdivised into distinct regions, the paleocortex (olfactory piriform cortex), the archicortex (including the hippocampus) and the neocortex. The neocortex which is positioned between the two other regions has a very sophisticated architecture, being organized radially into six layers, and tangentially into distinct areas that serve specialized functions, defined by differences in their cytoarchitecture, axonal connections and patterns of gene expression. Little is known today about the developmental mechanisms that control early cortex patterning.

Recent data obtained in the laboratory has shown that the doublesex/mab3 related-5 (DMRT5) transcription factor is expressed in a graded manner within cortical progenitors of the embryonic dorsal telencephalon, with the highest expression being detected in its caudomedial portion and that it plays an essential role in the initial regionalization of the cortical primordium. Given the importance of DMRT5 in the earliest steps of cortical development, we are using it as an entry point to better understand corticogenesis. Specifically, to study the mechanisms controling DMRT5 graded cortical expression, we are analysing its interactions with the other intrinsic transcription factors controling cortical identity and its transcriptional regulation in transgenic embryos. To better understand how it controls region-specific expression, we are engineering a transgenic mice that overexpress DMRT5 and study the consequence of its overexpression on the patterning of the cortex. Comparative genome-wide gene expression profiling of mouse cortex, using microarrays, following DMRT5 loss and gain of function will be also performed to identify DMRT5 targets. To determine whether Dmrt5 plays a role in neurogenesis, we will conditionally delete Dmrt5 after patterning is complete, and locally overexpress it in the cortical neuroepithelium using in utero electroporation. As Dmrt5 is also strongly expressed in ventral midbrain progenitors, the consequence of its invalidation on ventral mesencephalic neural fate specification is also under investigation. The results that will be obtained should provide novel insights into the mechanisms of forebrain and midbrain patterning, one of the key goals in developmental neurobiology.