Dmrt2 Orchestrates Neuronal Development in the Embryonic Cingulate Cortex: Unveiling Sex-Biased Vulnerabilities

Sexual differences are prevalent in the brain. DMRT family of transcription factors (TF) has been postulated as an important determinant of sex differences. Up to now, the role of DMRTs in the brain has been focused on the DMA subfamily. Here, we show an unprecedented role for Dmrt2 in regulating the proliferation and neuronal development of cortical neurons in mice. Dmrt2 expression is observed in deep-layer neurons of the cingulate cortex (CgCx) throughout development. Downregulation of Dmrt2 mRNA in the CgCx primordium results in premature cell cycle exit of embryonic progenitors and subsequent reduction in cortical plate cellular density at later developmental stages. Dmrt2 is expressed at higher levels in male embryos during early development, potentially explaining their increased vulnerability to Dmrt2 depletion. As development progresses, Dmrt2 expression is maintained in deeper-layer neurons, where this TF controls distinct terminal processes, including migration, axonal targeting, and neuronal-specific gene expression.

Our findings suggest a potential mechanistic link between the function of a Dmrt family member and sex-specific susceptibility to neurological disorders. This study expands our understanding of Dmrt gene function in the brain and provides insights into the molecular basis of sexual differences in neurodevelopmental processes.