The clathrin adaptor AP-1B independently controls proliferation and differentiation in the mammalian intestine

Maintenance of the polarity of the epithelial cells facing the lumen of the small intestine is crucial to ensure the vectorial absorption of nutrients as well as the integrity of the apical brush border and the intestinal barrier. Polarized vesicular trafficking plays a key role in this process, and defective transport due to mutations in apical trafficking-related genes has been shown to affect nutrient absorption. Interestingly, it has been demonstrated that downregulation of the polarized sorting clathrin adaptor AP-1B led to both epithelial polarity and proliferation defects in the mouse intestine. This enlightened a new function of polarized trafficking in the gut epithelium and a novel link between trafficking, polarity, and proliferation. Here, using CRISPR-Cas9-mediated mutation of the AP-1B coding gene Ap1m2 in mouse intestinal organoids, we uncovered a novel proliferation pathway controlled by AP-1B. We showed that the polarity defects induced by Ap1m2 mutations led to a defective apical targeting of both Rab11 ⁺ apical recycling endosomes and of the polarity determinant Cdc42. Moreover, we showed that these polarity defects were accompanied by an induction of YAP and EGFR/mTOR-dependent proliferation pathways. Finally, we showed that AP-1B additionally controlled a proliferation-independent differentiation pathway towards the secretory lineage. Overall, our results highlighted the pleiotropic roles played by AP-1B in the homeostasis of the gut epithelium.