Published in

Society for Neuroscience, Journal of Neuroscience, 42(38), p. 9105-9121, 2018

DOI: 10.1523/jneurosci.0375-18.2018

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DMRT5, DMRT3, and EMX2 Cooperatively Repress Gsx2 at the Pallium–Subpallium Boundary to Maintain Cortical Identity in Dorsal Telencephalic Progenitors

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Data provided by SHERPA/RoMEO

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 fingerdoublesexandmab-3 related(Dmrt) genes,Dmrt5(Dmrta2) andDmrt3, 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 ofDmrt3andDmrt5in 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 misexpressingDmrt5in 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 asGsx2, are upregulated in the dorsal telencephalon ofDmrt3;Dmrt5double KO embryos and downregulated when ventral telencephalic progenitors express ectopicDmrt5. Conditional overexpression ofDmrt5throughout the telencephalon produces gene expression and structural defects that are highly consistent with reduced GSX2 activity. Further,Emx2;Dmrt5double KO embryos show a phenotype similar toDmrt3;Dmrt5double KO embryos, and both DMRT3, DMRT5 and the homeobox transcription factor EMX2 bind to a ventral telencephalon-specific enhancer in theGsx2locus. Together, our findings uncover cooperative functions of DMRT3, DMRT5, and EMX2 in dividing dorsal from ventral in the telencephalon.SIGNIFICANCE STATEMENTWe 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, overexpressingDmrt5throughout 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.