DMRT5, DMRT3, and EMX2 Cooperatively RepressGsx2at the Pallium–Subpallium Boundary to Maintain Cortical Identity in Dorsal Telencephalic Progenitors

Abstract

Specification of dorsoventral regional identity in progenitors of the developing telencephalon is a first pivotal step in the development of the cerebral cortex and basal ganglia. Previously, we demonstrated that the two zinc finger and () genes, () and , which are coexpressed in high caudomedial to low rostrolateral gradients in the cerebral cortical primordium, are separately needed for normal formation of the cortical hem, hippocampus, and caudomedial neocortex. We have now addressed the role of and in controlling dorsoventral division of the telencephalon in mice of either sex by comparing the phenotypes of single knock-out (KO) with double KO embryos and by misexpressing in the ventral telencephalon. We find that DMRT3 and DMRT5 act as critical regulators of progenitor cell dorsoventral identity by repressing ventralizing regulators. Early ventral fate transcriptional regulators expressed in the dorsal lateral ganglionic eminence, such as , are upregulated in the dorsal telencephalon of double KO embryos and downregulated when ventral telencephalic progenitors express ectopic Conditional overexpression of throughout the telencephalon produces gene expression and structural defects that are highly consistent with reduced GSX2 activity. Further, double KO embryos show a phenotype similar to double KO embryos, and both DMRT3, DMRT5 and the homeobox transcription factor EMX2 bind to a ventral telencephalon-specific enhancer in the locus. Together, our findings uncover cooperative functions of DMRT3, DMRT5, and EMX2 in dividing dorsal from ventral in the telencephalon. We identified the DMRT3 and DMRT5 zinc finger transcription factors as novel regulators of dorsoventral patterning in the telencephalon. Our data indicate that they have overlapping functions and compensate for one another. The double, but not the single, knock-out produces a dorsal telencephalon that is ventralized, and olfactory bulb tissue takes over most remaining cortex. Conversely, overexpressing throughout the telencephalon causes expanded expression of dorsal gene determinants and smaller olfactory bulbs. Furthermore, we show that the homeobox transcription factor EMX2 that is coexpressed with DMRT3 and DMRT5 in cortical progenitors cooperates with them to maintain dorsoventral patterning in the telencephalon. Our study suggests that DMRT3/5 function with EMX2 in positioning the pallial-subpallial boundary by antagonizing the ventral homeobox transcription factor GSX2.

Dmrt factors determine the positional information of cerebral cortical progenitors via differential suppression of homeobox genes

“…Recently, Desmaris et al have reported a similar defect of dorsalventral patterning in Dmrt3/Dmrt5 and Emx2/Dmrt5 double mutants (Desmaris et al, 2018). This study is consistent with their previous report that Emx2 is a possible target of Dmrt5 (Saulnier et al, 2013).…”

Dmrt genes participate in the development of Cajal‐Retzius cells derived from the cortical hem in the telencephalon

“…The reason for this decrease could be related to developmental impairment of the medial part of the telencephalon. In accordance with the present results, previous studies have demonstrated malformation of caudomedial telencephalic structures in Dmrta2 and Dmrt3 KO mice . A question thus arises: when is the onset of defects in the medial telencephalon in Dmrt mutants?…”

“…It is reported that migration of CH‐derived CR cells to the lateral region in the cortex are regulated by guidance cues from the meninges and neurons derived from the neocortex . Since the neocortical area‐patterning and neurogenesis in Dmrt mutants are affected in depending on the Dmrt dosages, the neocortex lacking function of Dmrt may be an inhospitable environment for their migration.…”

Phylogenetic analysis and embryonic expression of panarthropod Dmrt genes

“…There, the gene is inter alia expressed in the central nervous system (CNS), nasal placodes, Müllerian ducts, forming somites, and the developing gonads (e.g. [66] Smith et al 2002, [67] Winkler et al 2004, [68] Desmaris et al 2018, [69] Yan et al 2018).…”