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The Mechanism of Dmrta2 / Dmrt5 and the Function of Dach1 in Cerebral Cortex Development

par Shen, Xueyi
Président du jury Vanhamme, Luc
Promoteur Bellefroid, Eric
Publication Non publié, 2024-08-22

Thèse de doctorat

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Résumé :

Elucidating the genetic control of cerebral cortex development is essential for understanding brain function, evolution, and disorders. During development, cortical progenitors acquire regionally restricted properties that control their maintenance or differentiation and determine the fate of their progeny. A set of transcription factors, expressed in gradients in the ventricular zone, provide positional information to progenitors, thus controlling their behavior and fate. While some transcription factors, such as Dmrta2, have been extensively studied and shown to play a key role in corticogenesis, the function of many others remains unknown. How the combination of these graded transcription factors operates and functions together to orchestrate the development of the cortex is a major question in developmental neuroscience that remains unanswered today. Here we have studied the mechanism of action of Dmrta2 and have approached the function of another conserved transcription factor, Dach1, expressed along a gradient similar to that of Dmrta2 but whose importance in cortical development has not yet been investigated. Our findings regarding Dmrta2 suggest that during the earliest stages of telencephalon development, it acts through the repression of the ventral homeobox gene, such as Gsx2, and that later, within the dorsal telencephalic compartment, it functions through the repression of another transcription factor, Pax6, thereby determining position information within cortical progenitors. These results show that Dmrta2 acts as a DNA-binding repressor, which is further supported by the identification of a point mutation in its DM domain that causes microcephaly in humans, and that it may act as a repressor by recruiting the NurD repressor complex. Additionally, our analysis of the consequences of the conditional loss of Dach1 in cerebral cortex development suggests that Dach1 also contributes to cortical patterning.