RT Journal Article SR Electronic T1 Evidence That Dmrta2 Acts through Repression of Pax6 in Cortical Patterning and Identification of a Mutation Impairing DNA Recognition Associated with Microcephaly in Human JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0377-24.2025 DO 10.1523/ENEURO.0377-24.2025 VO 12 IS 6 A1 Shen, Xueyi A1 Anirudhan, Jithu A1 Fatima, Ambrin A1 Plant, Estelle A1 Szemes, Tünde A1 Bouveret, Zélie A1 Keruzore, Marc A1 Kricha, Sadia A1 Nan, Xinsheng A1 Sabaté San José, Alba A1 Bianchin, Samuel A1 Veraghen, Bérénice A1 Delhaye, Louis-Paul A1 Mian, Bilal Ahmad A1 Khalid, Lubaba Bintee A1 Ali, Farhan A1 Zahra, Hijab A1 Ali, Asmat A1 Toft, Mathias A1 Dieu, Marc A1 Achouri, Younes A1 Li, Meng A1 Renard, Patricia A1 Van Lint, Carine A1 Poulard, Coralie A1 Iqbal, Zafar A1 Bellefroid, Eric J. YR 2025 UL http://www.eneuro.org/content/12/6/ENEURO.0377-24.2025.abstract AB Dmrta2 (also designated Dmrt5) is a transcriptional regulator expressed in cortical progenitors in a caudomedialhigh/rostrolaterallow gradient with important roles at different steps of cortical development. Dmrta2 has been suggested to act in cortex development mainly by differential suppression of Pax6 and other homeobox transcription factors such as the ventral telencephalic regulator Gsx2, which remains to be fully demonstrated. Here we have addressed the epistatic relation between Pax6 and Dmrta2 by comparing phenotypes in mutant embryos or embryos overexpressing both genes in various allelic combinations. We show that Dmrta2 cooperates with Pax6 in the maintenance of cortical identity in dorsal telencephalic progenitors and that it acts as a transcriptional repressor of Pax6 to control cortical patterning. Mechanistically, we show that in P19 cells, Dmrta2 acts as a DNA binding-dependent repressor on the Pax6 E60 enhancer and that a point mutation that affects its DNA binding properties identified in a consanguineous family leads to agenesis of the corpus callosum, pachygyria, and the absence of the cingulate gyrus. Finally, we provide evidence that Dmrta2 binds components of the NuRD repressor complex and interacts with zinc finger proteins such as Zfp423. Together, our results highlight the importance and conserved function of Dmrta2 in cortical development and provide novel insights into its mechanism of action.