DMRT5 Together with DMRT3 Directly Controls Hippocampus Development and Neocortical Area Map Formation

Abstract

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.

The doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1

“…The closely related Dmrt family member Dmrta1 was also up-regulated in Dmrta2 −/− NPCs, whereas no significant change was found for Dmrt3. In the reduced cortex of Dmrta2 conditional mutants, Dmrta2 and Dmrta1 also have been found to be up-regulated (14). Taken together, these observations further support a negative autoregulatory function for Dmrta2, as well as regulatory interactions with other Dmrt family members.…”

“…This is of particular interest because of the similar expression patterns of Dmrt3, Dmrta1, and Dmrta2 in the dorsal telencephalon, suggesting a potential for functional redundancy (13,24). A similar but less severe phenotype as that seen in Dmrta2 null mutants has been observed in mice with a Dmrt3 null mutation, further supporting the idea that the two factors have overlapping functions in cortical development (12)(13)(14). In contrast, Dmrta1-null mice produce viable offspring with no overt anatomic defects in the brain (13,44).…”

“…Dmrta2 loss of function in zebrafish leads to significant reductions in cortical size, coupled with reduced neuronal numbers (10,11). Likewise, a smaller neocortex, particularly the dorsomedial neocortex, has been observed in mice carrying null deletions of Dmrta2 (12)(13)(14). Together with the association of DMRTA2 mutation and microlissencephaly in humans, these findings implicate Dmrta2 as an important regulator for cortical neurogenesis.…”

“…Recently, conditional Dmrta2 mutant mice (Dmrta2 fl/fl ;Emx1-cre) were created that delete Dmrta2 in cortical progenitors after cortical hem formation without impacting Wnt signaling. The Dmrta2 cKO embryos also show reduced cortical hemisphere size, suggesting a direct role of Dmrta2 in the control of NPC behavior (14). Cells in a monolayer ESC-neural differentiation system are generally exposed to the same extracellular environment and do not form "signaling centers," unlike those found in the developing brain.…”

“…This excess neuronal production during early neurogenesis may be a secondary consequence of the reduction of Wnt cortical hem signals or a direct consequence of the loss of Dmrta2 in cortical progenitors (12). To test this latter possibility, we used immunostaining to assay the amount of Tubb3 + and Eomes + cells in the cortical plate of E11 conditional Dmrta2 mutant mice (Dmrta2 fl/fl ;Emx1-cre), in which the Wnt signaling pathway appears to be unaffected (14). We found increased numbers of Tubb3 + and Eomes + cells in the conditional Dmrta2 mutant mice relative to controls (Fig.…”