DMRT5, DMRT3, and EMX2 cooperatively repress GSX2 at the pallium–subpallium boundary to maintain cortical identity in dorsal telencephalic progenitors

Elodie Desmaris, Marc Keruzore, Amandine Saulnier, Leslie Ratié, Stavroula Assimacopoulos, Sarah De Clercq, Xinsheng Nan, Kaushik Roychoudhury, Shenyue Qin, Sadia Kricha, Clément Chevalier, Thomas Lingner, Kristine A. Henningfeld, David Zarkower, Antonello Mallamaci, Thomas Theil, Kenneth Campbell, Tomas Pieler, Meng Li, Elizabeth A. GroveEric J. Bellefroid

Research output: Contribution to journalArticle

6 Scopus citations

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 doublesex and mab-3 related (Dmrt) genes, Dmrt5 (Dmrta2) and Dmrt3, 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 Dmrt3 and Dmrt5 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 Dmrt5 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 Gsx2, are upregulated in the dorsal telencephalon of Dmrt3;Dmrt5 double KO embryos and downregulated when ventral telencephalic progenitors express ectopic Dmrt5. Conditional overexpression of Dmrt5 throughout the telencephalon produces gene expression and structural defects that are highly consistent with reduced GSX2 activity. Further, Emx2;Dmrt5 double KO embryos show a phenotype similar to Dmrt3;Dmrt5 double KO embryos, and both DMRT3, DMRT5 and the homeobox transcription factor EMX2 bind to a ventral telencephalon-specific enhancer in the Gsx2 locus. Together, our findings uncover cooperative functions of DMRT3, DMRT5, and EMX2 in dividing dorsal from ventral in the telencephalon.

Original languageEnglish (US)
Pages (from-to)9105-9121
Number of pages17
JournalJournal of Neuroscience
Volume38
Issue number42
DOIs
StatePublished - Oct 17 2018

Keywords

  • Dmrt
  • Dorsoventral patterning
  • Emx2
  • Gsx2
  • Pallium
  • Subpallium boundary
  • Telencephalon

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    Desmaris, E., Keruzore, M., Saulnier, A., Ratié, L., Assimacopoulos, S., De Clercq, S., Nan, X., Roychoudhury, K., Qin, S., Kricha, S., Chevalier, C., Lingner, T., Henningfeld, K. A., Zarkower, D., Mallamaci, A., Theil, T., Campbell, K., Pieler, T., Li, M., ... Bellefroid, E. J. (2018). DMRT5, DMRT3, and EMX2 cooperatively repress GSX2 at the pallium–subpallium boundary to maintain cortical identity in dorsal telencephalic progenitors. Journal of Neuroscience, 38(42), 9105-9121. https://doi.org/10.1523/JNEUROSCI.0375-18.2018