Revisiting the role of GCNF in embryonic development.

GCNF (NR6A1) is essential for embryonic development. GCNF belongs to the nuclear receptor (NR) gene family, it is distantly related to other NRs and is the only member of subfamily 6. As the ligand for GCNF has not been identified, GCNF is designated an orphan nuclear receptor. GCNF has been found to be a transcriptional repressor, through specific binding to DR0 response elements, which is found in the Oct4 proximal promoter for example. GCNF is expressed widely in early mouse embryos, and later in the developing nervous system. GCNF knockout mouse embryos die around E10.5. GCNF is required for the restriction of Oct4 expression to primordial germ cells after gastrulation. GCNF is expressed in ES/EC cells and during their differentiation, and has been reported to be required for pluripotency gene repression during retinoic acid (RA)-induced mES cell differentiation. GCNF can interact with DNA methylation proteins, and is suggested to recruit DNA methylation complexes to repress and silence Oct4 expression. Nuclear receptor regulation in embryonic development is a complex process, as different nuclear receptors have overlapping and distinct functions. In-depth exploration of GCNF function and mechanism of action will help to comprehensively understand the nuclear receptor regulation in embryonic development.