Lineage commitment of pluripotent cells is a critical step in the development of multicellular organisms and a prerequisite for efficient differentiation of stem cells into terminal cell types. During successful neuroectodermal lineage commitment, extracellular signals terminate the pluripotency program, activate neural transcriptional program, and suppress alternative mesendodermal fate. Retinoic acid (RA) has been identified as a potent inducer of neural differentiation in embryonic stem cells (ESCs), yet the transcriptional program initiated by RA is poorly understood. Expression profiling of differentiating ESCs revealed delayed response of the pluripotency marker Oct4 and neural marker Sox1 following RA treatment, suggesting that RA regulates the pluripotency program and neural transcriptional program indirectly through induction of additional transcription factors. In this study, I identified a zinc finger factor Zfp703 as a downstream effector of RA-mediated neuroectodermal lineage commitment.

Zfp703 expression in ESCs resulted in Oct4 repression, Sox1 induction, and neural differentiation. Moreover, Zfp703 strongly suppresses mesendodermal fate by repressing genes such as Brachyury, Eomes, and Mixl1 even under conditions favoring mesendoderm specification. Zfp703 binds to and represses Lef1 promoter, raising the possibility that it might modulate Wnt signaling via regulating Lef1. Finally, Zfp703 is not required for RA-mediated Oct4 repression and Sox1 induction. However, it is necessary for efficient Brachyury repression by RA. Based on these data, I propose that Zfp703 is involved in the transcription regulation during neural progenitor specification. Through downregulating of both mesendodernal fate and pluripotency, Zfp703 de-represses neural transcriptional program and indirectly promotes the default neuroectodermal lineage commitment.