Sox17 plays a substantial role in late-stage differentiation of the extraembryonic endoderm in vitro.

Sox17 is a Sry-related HMG-box transcription factor developmentally expressed in both the definitive endoderm and extraembryonic endoderm (ExE). Although Sox17(-/-) mouse embryos have a defective definitive gut endoderm, their developing ExE is morphologically intact. Here, we aimed to investigate the role of Sox17 in ExE development by using an in vitro differentiation system of embryonic stem cells (ESCs). Although forced Sox17 expression in ESCs did not affect ExE commitment, it facilitated the differentiation of ESC-derived primitive endoderm cells into visceral and parietal endoderm cells. This event was inhibited by the forced expression of Nanog, a negative regulator of differentiation of ESCs into the ExE. Although Sox17(-/-) ESCs could differentiate into primitive endoderm cells, further differentiation was severely impaired. These results indicate a substantial involvement of Sox17 in the late stage of ExE differentiation in vitro. Furthermore, the expression of Sox7--another Sox factor, concomitantly expressed with Sox17 in the developing ExE--was suppressed during the in vitro differentiation of Sox17(-/-) ESCs, but it was maintained at a high level in the extraembryonic tissues of Sox17(-/-) embryos. These findings possibly explain the discrepancy between the ExE phenotype derived from Sox17(-/-) ESCs and that of Sox17(-/-) embryos.