TY - JOUR
T1 - DMRT5, DMRT3, and EMX2 cooperatively repress GSX2 at the pallium–subpallium boundary to maintain cortical identity in dorsal telencephalic progenitors
AU - Desmaris, Elodie
AU - Keruzore, Marc
AU - Saulnier, Amandine
AU - Ratié, Leslie
AU - Assimacopoulos, Stavroula
AU - De Clercq, Sarah
AU - Nan, Xinsheng
AU - Roychoudhury, Kaushik
AU - Qin, Shenyue
AU - Kricha, Sadia
AU - Chevalier, Clément
AU - Lingner, Thomas
AU - Henningfeld, Kristine A.
AU - Zarkower, David
AU - Mallamaci, Antonello
AU - Theil, Thomas
AU - Campbell, Kenneth
AU - Pieler, Tomas
AU - Li, Meng
AU - Grove, Elizabeth A.
AU - Bellefroid, Eric J.
N1 - Publisher Copyright:
© 2018 the authors.
PY - 2018/10/17
Y1 - 2018/10/17
N2 - 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.
AB - 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.
KW - Dmrt
KW - Dorsoventral patterning
KW - Emx2
KW - Gsx2
KW - Pallium
KW - Subpallium boundary
KW - Telencephalon
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UR - http://www.scopus.com/inward/citedby.url?scp=85055211144&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0375-18.2018
DO - 10.1523/JNEUROSCI.0375-18.2018
M3 - Article
C2 - 30143575
AN - SCOPUS:85055211144
SN - 0270-6474
VL - 38
SP - 9105
EP - 9121
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 42
ER -