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 language | English (US) |
|---|---|
| Pages (from-to) | 9105-9121 |
| Number of pages | 17 |
| Journal | Journal of Neuroscience |
| Volume | 38 |
| Issue number | 42 |
| DOIs | |
| State | Published - Oct 17 2018 |
Bibliographical note
Funding Information:This work was supported by Fonds National de la Recherche Scientifique Grants FRFC 6973823 and CDR 29148846, Walloon Region First International Project “CORTEX,” and Fonds pour la Recherche Médicale dans le Hainaut. Work in the laboratories of E.A.G., D.Z., and K.C. was supported by National Institutes of Health Grants RO1 MH103211, GM059152, and R01 NS044080, respectively. Work in the laboratory of T.T. was supported by Grant BB/P00122X/1 by the Biotechnology and Biological Sciences Research Council. Work in the Center for Microscopy and Molecular Imaging was supported by the Hainaut-Biomed FEDER program. E.D. is a Wallonie-Bruxelles International doctoral fellow from the Wallonia-Brussels Federation. M.K. was a First International and L.R. a BEWARE postdoctoral fellow from the Walloon Region. S.D.C. was a Fonds National de la Recherche Scientifique postdoctoral fellow. We thank Dr. Daichi Kawaguchi for the kind gift of the Foxg1-IRES-Cre line used in this study; Dr. François Guillemot, John Rubenstein, Setsuko Sahara, Denis O’Leary, Anne Chotteau-Lelièvre, and Y. Sun for gifts of plasmid DNA; Carlos Parras for the Ascl1 antibody; and Louis Delhaye for technical help.
Funding Information:
Received Feb. 7, 2018; revised April 23, 2018; accepted Aug. 15, 2018. Author contributions: E.D., M.K., A.S., E.A.G. and E.J.B. designed research; E.D., M.K., A.S., L.R., S.A., S.D.C., X.N., K.R.,S.Q.,andS.K.performedresearch;E.D.,M.K.,A.S.,L.R.,S.A.,S.D.C.,X.N.,K.R.,S.Q.,C.C.,T.L.,K.A.H.,E.A.G.,and E.J.B. analyzed data; E.D., E.J.B., and E.A.G. wrote the paper. K.A.H., D.Z., A.M., T.T., K.C., T.P., and M.L. edited the paper and/or contributed to reagents/analytic tools. This work was supported by Fonds National de la Recherche Scientifique Grants FRFC 6973823 and CDR 29148846, Walloon Region First International Project “CORTEX,” and Fonds pour la Recherche Médicale dans le Hainaut.WorkinthelaboratoriesofE.A.G.,D.Z.,andK.C.wassupportedbyNationalInstitutesofHealthGrantsRO1 MH103211, GM059152, and R01 NS044080, respectively. Work in the laboratory of T.T. was supported by Grant BB/P00122X/1 by the Biotechnology and Biological Sciences Research Council. Work in the Center for Microscopy and Molecular Imaging was supported by the Hainaut-Biomed FEDER program. E.D. is a Wallonie-Bruxelles International doctoral fellow from the Wallonia-Brussels Federation. M.K. was a First International and L.R. a BEWARE postdoctoralfellowfromtheWalloonRegion.S.D.C.wasaFondsNationaldelaRechercheScientifiquepostdoctoral fellow. We thank Dr. Daichi Kawaguchi for the kind gift of the Foxg1-IRES-Cre line used in this study; Dr. François Guillemot,JohnRubenstein,SetsukoSahara,DenisO’Leary,AnneChotteau-Lelièvre,andY.Sunforgiftsofplasmid DNA; Carlos Parras for the Ascl1 antibody; and Louis Delhaye for technical help. The authors declare no competing financial interests. *M.K. and A.S. contributed equally to this work. Correspondenceshouldbeaddressedtoeitherofthefollowing:Dr.EricJ.Bellefroid,UniversitéLibredeBruxelles, Institute of Neuroscience, B-6041 Gosselies, Belgium, E-mail: [email protected]; or Dr. Elizabeth A. Grove, Department of Neurobiology, University of Chicago, Chicago, IL 60637, E-mail: [email protected]. DOI:10.1523/JNEUROSCI.0375-18.2018 Copyright © 2018 the authors 0270-6474/18/389106-17$15.00/0
Publisher Copyright:
© 2018 the authors.
Keywords
- Dmrt
- Dorsoventral patterning
- Emx2
- Gsx2
- Pallium
- Subpallium boundary
- Telencephalon