Ligand-Dependent Corepressor (LCoR) Is a Rexinoid-Inhibited Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor α Coactivator

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is an essential regulator of placental development. To gain deeper insights into placental PPAR gamma signaling, we dissected its regulation of the Muc1 promoter. We find that, unlike prototypic target activation by heterodimeric receptors, which is either stimulated by or refractory to retinoid X receptor (RXR) ligands (rexinoids), the induction of Muc1 by liganded PPAR gamma requires RXR alpha but is inhibited by rexinoids. We demonstrate that this inhibition is mediated by the activation function 2 (AF2) domain of RXR alpha and that Muc1 activation entails altered AF2 structures of both PPAR gamma and RXR alpha. This unique regulation of Muc1 reflects specific coactivation of PPAR gamma-RXR alpha heterodimers by the transcription cofactor ligand-dependent corepressor (LCoR), corroborated by significant downregulation of Muc1 in Lcor-null placentas. LCoR interacts with PPAR gamma and RXR alpha in a synergistic fashion via adjacent non-canonical protein motifs, and the AF2 domain of ligand-bound RXR alpha inhibits this interaction. We further identify the transcription factor Kruppel-like factor 6 (KLF6) as a critical regulator of placental development and a component of Muc1 regulation in cooperation with PPAR gamma, RXR alpha, and LCoR. Combined, these studies reveal new principles and players in nuclear receptor function in general and placental PPAR gamma signaling in particular.