AP-1B Controls Several Levels of Cell Proliferation and Differentiation in Mouse Enteroids

Abstract

Gut homeostasis relies on the tightly controlled balance between intestinal stem cell self-renewal and differentiation. The clathrin adaptor complex AP-1B plays a pivotal role in establishing the polarity of enterocytes as well as in the asymmetric distribution of membrane proteins, including the brush border transporters that govern intestinal absorption. Additionally, AP-1B has been involved in the control of intestinal cell proliferation, which suggests that it may regulate various aspects of gut functional organisation. In this study, we investigated the consequences of conditional mutations of the gene encoding the AP-1B subunit μ1B (Ap1m2) in mouse enteroids. We first showed in this model that Ap1m2 mutations also induce strong polarity defects at the subcellular level in the absorptive enterocytes. Next, we unveiled that AP-1B regulates intestinal cell differentiation at the tissular level, through the commitment of stem/progenitor cells towards the secretory lineage and cell positioning along the crypt-villus axis. Furthermore, we showed that AP-1B inhibition also induces hyperproliferation in enteroids. Notably, we unravelled that, complementary to the Wnt/β-catenin-mediated proliferation described in null mice, AP-1B downregulation triggers a tissue-autonomous, mTOR/YAP-dependent, proliferative pathway. Overall, these results enlighten the pleiotropic roles played by AP-1B in the homeostasis of the gut epithelium.