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

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 hESC organoid system, we demonstrate that both pancreas budding and specification are induced by RAR:RXR signalling. 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 of how 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.