Mice that are constitutively null for the zinc finger doublesex and mab-3 related (Dmrt) gene, Dmrt5/Dmrta2, show a variety of patterning abnormalities in the cerebral cortex, including the loss of the cortical hem, a powerful cortical signaling center. In conditional Dmrt5 gain of function and loss of function mouse models, we generated bidirectional changes in the neocortical area map without affecting the hem. Analysis indicated that DMRT5, independent of the hem, directs the rostral-to-caudal pattern of the neocortical area map. Thus, DMRT5 joins a small number of transcription factors shown to control directly area size and position in the neocortex. Dmrt5 deletion after hem formation also reduced hippocampal size and shifted the position of the neocortical/paleocortical boundary. Dmrt3, like Dmrt5, is expressed in a gradient across the cortical primordium. Mice lacking Dmrt3 show cortical patterning defects akin to but milder than those in Dmrt5 mutants, perhaps in part because Dmrt5 expression increases in the absence of Dmrt3. DMRT5 upregulates Dmrt3 expression and negatively regulates its own expression, which may stabilize the level of DMRT5. Together, our findings indicate that finely tuned levels of DMRT5, together with DMRT3, regulate patterning of the cerebral cortex.
Bibliographical noteFunding Information:
This work was supported by grants from the FNRS (FRFC 6973823), the Walloon Region (First International project “CORTEX), the Wiener-Anspach Foundation, and the Fonds pour la Recherche Médicale dans le Hainaut (FMRH), Hoguet, J. Brachet et David et Alice Van Buuren to E.B. Work in the laboratories of E.A.G. and D.Z. was supported by NIH grants MH103211 and GM15952, respectively. S.D.C. was a FNRS postdoctoral fellow, M.K. a First International postodoctoral fellow, J.P. a FNRS doctoral fellow, and C.K.M. a NSF predoctoral fellow. E.D. is supported by a Wallonie-Bruxelles International (WBI) doctoral fellowship.
The authors acknowledge S. Garel, P. Vanderhaeghen for providing the Wnt3a-IRES-Cre (this line was generated by M. Yoshida in the laboratory of E. Grove), Emx1-IRES-Cre, and Nestin-IRES-Cre mouse lines, M. Li for providing the DMRT5 antibody, and S. Tole for providing plasmids. We are grateful to S. Kricha for technical assistance and L. Delhaye for animal care and genotyping. Fluorescence microscopy images were taken at the Center for Microscopy and Molecular Imaging (CMMI), which is supported by the Hainaut-Biomed FEDER program. Conflict of Interest: None declared.
- cortical hem
- neocortical area map
- transcription factor