Foxd3 suppresses NFAT-mediated differentiation to maintain self-renewal of embryonic stem cells.

Pluripotency-associated transcription factor Foxd3 is required for maintaining pluripotent cells. However, molecular mechanisms underlying its function are largely unknown. Here, we report that Foxd3 suppresses differentiation induced by calcineurin-NFAT signaling to maintain the ESC identity. Mechanistically, Foxd3 interacts with NFAT proteins and recruits co-repressor Tle4, a member of the Tle repressor family highly expressed in undifferentiated ESCs, to suppress NFATc3's transcriptional activities. Furthermore, global transcriptome analysis shows that Foxd3 and NFATc3 co-regulate a set of differentiation-associated genes in ESCs. Collectively, our study establishes a molecular and functional link between a pluripotency-associated factor and an important ESC differentiation-inducing pathway.