Parallel regulation of tissue morphogenesis and cell-fate specification by RAR:RXR signaling during pancreas formation.

Abstract

During embryogenesis, morphologically diverse epithelial organs bud from different regions of the embryonic gut. The unique features of each nascent organ result from distinct cell fate specification and morphogenetic events elicited by organ-inducing cues. Retinoic acid is a powerful inducer of the pancreas, yet how it regulates pancreas specification and budding from the foregut endoderm remains poorly understood. By modeling these processes using a new human embryonic stem cell (hESC) organoid system, we demonstrate that both pancreas budding and specification are induced by RAR:RXR signaling. On the molecular level, we identify β-catenin as an important downstream target and propose that the reduction of β-catenin at the cell membrane weakens cell-cell adhesion (resulting in perturbed apical-basal cell polarity and gut epithelium multi-layering), while its nuclear depletion relieves β-catenin-mediated repression of FOXA2-dependent Pdx1 transcriptional activation. Our findings provide a new framework by which developmental cues coordinate both morphogenetic and cell specification events by targeting proteins with dual roles in cell-cell adhesion and transcription, such as β-catenin.