Nuclear Receptors in Regulation of Mouse ES Cell Pluripotency and Differentiation

Abstract

Embryonic stem (ES) cells have great therapeutic potential because they are capable of indefinite self-renewal and have the potential to differentiate into over 200 different cell types that compose the human body. The switch from the pluripotent phenotype to a differentiated cell involves many complex signaling pathways including those involving LIF/Stat3 and the transcription factors Sox2, Nanog and Oct-4. Many nuclear receptors play an important role in the maintenance of pluripotence (ERRbeta, SF-1, LRH-1, DAX-1) repression of the ES cell phenotype (RAR, RXR, GCNF) and also the differentiation of ES cells (PPARgamma). Here we review the roles of the nuclear receptors involved in regulating these important processes in ES cells.

Figure 1

Yin-yang regulation of Oct-4 expression during ES cell differentiation by LRH-1 and GCNF, which compete for the same element. In undifferentiated ES cells LRH-1 binds to elements in the Oct-4 proximal enhancer and proximal promoter to maintain its expression during the very earliest stages of differentiation. As differentiation progresses LRH-1 expression decreases and GCNF expression is induced. At an intermediate point GCNF displaces LRH-1 and represses Oct-4 by recruiting the DNA methylation machinery that ultimately leads to the silencing of Oct-4 expression in somatic cells.