In the developing mammalian telencephalon, progenitor cells give rise to diverse subtypes of glutamatergic and GABAergic neurons in the dorsal and ventral telencephalon, respectively. It is well known that the antagonistic action of sonic hedgehog (Shh) and Wnt signaling plays a critical role in the dorso-ventral specification of neural progenitor cells through regulating the expression of several transcription factors. However, given the complexity of the temporal and regional regulation of corticogenesis, there seem to be missing links in the signaling network regulating neocortical development. Here, we report that Dmrt3 and Dmrta2, two related mammalian DM domain-containing transcription factors (Dmrt), are critically involved in maintaining the neocortical identity of neural progenitor cells in the developing mouse brain. These factors are highly expressed in neural progenitor cells in the dorsal telencephalon at early stages of cortical development. Dmrt3/Dmrta2 double mutant brains exhibited a conversion of neural progenitor characteristics in the dorsal telencephalon from a neocortical (glutamatergic neuron-generating) to a subcortical (GABAergic neuron-generating) identity, suggesting that Dmrt3/Dmrta2 negatively regulate the genetic pathway, establishing the ventral cell fate in the telencephalon. Consistent with this, our gene expression profiling of mutant brains and ChIP-seq analyses revealed that Dmrt3/Dmrta2 directly suppress the expression of the homeobox protein Gsx2. Gsx2 plays a pivotal role in generating olfactory bulb GABAergic interneurons by upregulating the zinc-finger transcription factor Sp8 in the PSB (pallial-subpallial boundary) and dLGE (dorsal lateral ganglionic eminence) regions of the telencephalon. Consistent with this, Sp8 was also upregulated ectopically in the dorsal telencephalon of Dmrt mutant brains. This phenotype was partially rescued by the conditional ablation of Shh in Dmrt3/Dmrt2 double mutant brains. Our results indicate that Dmrt3/Dmrta2 act as critical players in generating neocortical excitatory neurons by suppressing the Gsx2-Sp8 cascade promoted by Shh signaling at the progenitor level. Our results suggest a novel mechanism for maintaining neural progenitor characteristics, in which Dmrt3/Dmrta2 selectively blocks Shh-dependent ventralization of neural progenitors, thereby ensuring the proper development of neocortical neural progenitors.

研究助成：Research funds : KAKENHI (25123724) (24500395)