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

• Published in: Developmental biology 2023-07, Vol.499, p.59-74
• Main Authors: Barlow, Haley R., Ahuja, Neha, Bierschenk, Tyler, Htike, Yadanar, Fassetta, Luke, Azizoglu, D. Berfin, Flores, Juan, Gao, Nan, De la O, Sean, Sneddon, Julie B., Marciano, Denise K., Cleaver, Ondine
• Format: Article
• Language: English
• Subjects: AMIS; Animals; Cell Membrane - metabolism; Cell polarity; Cell shape; Crbs3; Endocrine cell; Epithelium; Epithelium - metabolism; Lumen formation; Mice; Morphogenesis; Mucin-1; Pancreas; Pancreas - metabolism; Par3/6; Protein Isoforms - metabolism; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; Rab11
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2023.05.002

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 processes depend on proper lumenogenesis. The Rab GTPase Rab11 is essential for 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 for 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 both Rab11A and Rab11B in the embryonic pancreas results in morphogenetic defects of the epithelium, including defective lumen formation and lumen interconnection. In contrast to wildtype cells, Rab11pancDKO cells initiate the formation of multiple ectopic lumens, resulting in a failure to coordinate a single apical membrane initiation site (AMIS) between groups of cells. This results in an inability to form ducts with continuous lumens. Here, we show that these defects are due to failures in vesicle trafficking, as apical and junctional components remain trapped within Rab11pancDKO cells. Together, these observations suggest that 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. [Display omitted] •Rab11Af/f;Rab11B−/-;Pdx1-Cre pancreas displays disruption of epithelial organization and reduction of endocrine cell mass.•Loss of Rab11 results in disruption of pancreatic lumen continuity due to a failure of lumen formation.•Epithelial cells lacking Rab11 display abnormal polarity.