Myosin VB is Critical for Progenitor Cell Function in the intestine

Microvillus inclusion disease (MVID) is a congenital diarrheal disorder, caused by inactivating mutations in myosin Vb (MYO5B). MYO5B deficient mice and cell lines have demonstrated the importance of MYO5B in enterocyte brush border development; however, the previous MYO5B knockout models lacked specificity to the stem cell function. To address the direct impact of MYO5B loss on the epithelial stemness, we investigated the effects of progressive MYO5B deficiency originating in mouse intestinal crypt cells. Our transcriptomic and multi-plex immunostaining datasets demonstrate that MYO5B is critical for intestinal stem cell identity. MYO5B-deficient crypts acquire a hyperproliferative phenotype and lack the ability of proper cell lineage differentiation. An evident disruption in mitochondrial structure and fatty acid metabolism likely underlies these crypt deficits. Consistent with mouse models, MVID patient biopsies demonstrate abnormal expansion of proliferative zone besides villus blunting. These data reveal the direct impacts of MYO5B loss on intestinal epithelial cell progenitor functions.