The Mammalian DM Domain Transcription Factor Dmrta2 Is Required for Early Embryonic Development of the Cerebral Cortex

Abstract

Development of the mammalian telencephalon is precisely organized by a combination of extracellular signaling events derived from signaling centers and transcription factor networks. Using gene expression profiling of the developing mouse dorsal telencephalon, we found that the DM domain transcription factor Dmrta2 (doublesex and mab-3-related transcription factor a2) is involved in the development of the dorsal telencephalon. Consistent with its medial-high/lateral-low expression pattern in the dorsal telencephalon, Dmrta2 null mutants demonstrated a dramatic reduction in medial cortical structures such as the cortical hem and the choroid plexus, and a complete loss of the hippocampus. In this mutant, the dorsal telencephalon also showed a remarkable size reduction, in addition to abnormal cell cycle kinetics and defective patterning. In contrast, a conditional Dmrta2 deletion in the telencephalon, which was accomplished after entry into the neurogenic phase, resulted in only a slight reduction in telencephalon size and normal patterning. We also found that Dmrta2 expression was decreased by a dominant-negative Tcf and was increased by a stabilized β-catenin form. These data suggest that Dmrta2 plays pivotal roles in the early development of the telencephalon via the formation of the cortical hem, a source of Wnts, and also in the maintenance of neural progenitors as a downstream of the Wnt pathway.

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

“…1 B and D). During development, Dmrta2 expression is restricted to the dorsal telencephalon, where it is coexpressed with Pax6 but in an opposite gradient (12,13,24). Consistent with its expression in vivo, we found that Dmrta2 and Pax6 staining largely overlapped in ESC-derived NPCs localized in neural rosettes, from which Eomes + basal progenitor cells could be seen extending distally (Fig.…”

“…Although Dmrt1 is not expressed by cortical NPCs, our data suggest significant overlaps in the regulatory targets of different Dmrt proteins. 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).…”

“…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.…”

“…Loss-of-function mutations in Dmrta2 have been linked with microcephaly in zebrafish, mice, and humans (7,(10)(11)(12)(13); however, the role and mechanism of action of Dmrta2 in the control of NPC maintenance and expansion have remained unknown until now. 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.…”

“…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).…”