Novel Insights into Emx2 and Dmrta2 Cooperation during Cortex Development and Evidence for Dmrta2 Function in the Choroid Plexus

Early dorsal telencephalon development is coordinated by an interplay of transcription factors that exhibit a graded expression pattern in neural progenitors. How they function together to orchestrate cortical development remains largely unknown. The Emx2 and Dmrta2 genes encode transcription factors that are expressed in a similar caudomedial high /rostrolateral low gradient in the ventricular zone of the developing dorsal telencephalon with, in the medial pallium, Dmrta2 but not Emx2 expressed in the developing choroid plexus (ChP). Their constitutive loss has been shown to impart similar cortical abnormalities, and their combined deletion exacerbates the phenotypes, suggesting possible cooperation during cortex development. In this study, using embryos of both sexes, we utilized molecular and genetic approaches to dissect how Emx2 functions with Dmrta2 during mouse cortical development. Our results show that while they regulate a similar set of genes, their common direct targets are limited but include key regulators of cortical development. The identification of the interaction partners of Emx2 suggests that it coordinates with the LIM domain-binding protein Ldb1 to execute the activation and repression of some of its downstream targets. Finally, while Emx2 is known to suppress ChP development, we also provide evidence that Dmrta2 is, in contrast, required for ChP since in its absence in medial telencephalic progenitors, mice develop hydrocephalus postnatally, a phenotype that appears to be due to a compromised cytoarchitecture. Together, these data indicate that Emx2 and Dmrta2 have similar but also distinct functions in telencephalon development and provide the first insights into Emx2 mechanism of action.