Rab11 is essential to pancreas morphogenesis, lumen formation and endocrine mass.

Abstract

The molecular links between tissue-level morphogenesis and the differentiation of cell lineages in the pancreas remain elusive despite a decade of studies. We previously showed that in pancreas both these processes depend on proper lumenogenesis. The Rab GTPase Rab11 has been shown to be essential to epithelial lumen formation in vitro, however few studies have addressed its functions in vivo and none have tested its requirement in pancreas. Here, we show that Rab11 is critical to proper pancreas development. Co-deletion of the Rab11 isoforms Rab11A and Rab11B in the developing pancreatic epithelium (Rab11pancDKO) results in ~50% neonatal lethality, and surviving adult Rab11pancDKO mice exhibit defective endocrine function. Loss of Rab11 in the embryonic pancreas results in morphogenetic defects of the epithelium linked to defective lumen formation and interconnection. In contrast to wildtype cells, Rab11pancDKO cells attempt to form multiple lumens, resulting in a failure to coordinate a single apical membrane initiation site (AMIS) between groups of cells. We show that these defects are due to failures in vesicle trafficking, as apical components remain trapped within Rab11pancDKO cells. Together, these observations suggest Rab11 directly regulates epithelial lumen formation and morphogenesis. Our report links intracellular trafficking to organ morphogenesis in vivo, and presents a novel framework for decoding pancreatic development. HIGHLIGHTSO_LIRab11Af/f;Rab11B-/-;Pdx1-Cre pancreas displays disruption of epithelial organization and reduction of endocrine cell mass. C_LIO_LILoss of Rab11 results in disruption of pancreatic lumen continuity due to a failure of lumen formation. C_LIO_LIEpithelial cells lacking Rab11 display abnormal polarity. C_LI