Brd2 is required for cell cycle exit and neuronal differentiation through the E2F1 pathway in mouse neuroepithelial cells.

To understand genetic programs controlling mammalian central nervous system (CNS) development, we have identified one transgene-inserted mutation, which showed embryonic lethality during neurulation. Determination of the transgene integration site and rescue experiments revealed that the Brd2 gene, whose products specifically bind acetylated histone H4 and can mediate transcription, was the cause of this mutation. Expression studies with specific markers demonstrated that cell cycle progression was accelerated and neuronal differentiation as well as cell cycle exit were impaired in Brd2-deficient neruoepithelial cells. To investigate whether Brd2 regulates neuronal differentiation through a E2F1 transcriptional factor, which directly binds Brd2 and controls genes expression for cell cycle progression and exit, we analyzed Brd2;E2F1 double mutant phenotypes and, consequently found that abnormalities in neuronal differentiation and cell cycle progression due to Brd2-deficiency were restored by removing the E2F1 gene. These findings suggest that Brd2 is required for cell cycle exit and neuronal differentiation of neuroepithelial cells through the E2F1 pathway during mouse CNS development.

Crucial roles of Foxa2 in mouse anterior-posterior axis polarization via regulation of anterior visceral endoderm-specific genes.

Anterior visceral endoderm (AVE) plays essential roles with respect to anterior-posterior axis development in the early mouse embryo. To assess the genetic cascade involved in AVE formation, the cis-regulatory elements directing expression of vertebrate Otx2 genes in the AVE were analyzed via generation of transgenic mice. Otx2 expression in AVE is regulated directly by the forkhead transcription factor, Foxa2. Moreover, Foxa2 is essential for expression of the Wnt antagonists, Dkk1 and Cerl, in visceral endoderm during the pre- to early streak stages; however, Foxa2 appears to be dispensable for subsequent Dkk1 expression associated with forebrain induction. Thus, we propose that Foxa2 is crucial in early anterior-posterior axis polarization in terms of regulation of expression of AVE-specific genes. These findings provide profound insights into conserved roles of Foxa2 transcription factors in anterior specification throughout the evolution of the chordate body plan.