Regionally defined stem cell growth directs cell fate during intestinal nutrient adaptation

The adult intestine is a regionalized organ, whose size and cellular composition is adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling integrates with mechanisms controlling cell fate to achieve regional changes in intestinal cell composition remains unclear. Here we show that nutrient adaptation involves highly region-specific control of intestinal cell size, number and differentiation. Our data uncovered a mechanism by which mTOR complex 1 activation increases ISC size in a region-specific manner. This promotes Delta expression to direct cell fate towards the absorptive enteroblast lineage, while inhibiting secretory enteroendocrine cell differentiation. Thus, ISC size acts as an early fate determinant allowing regional control of intestinal cell differentiation in response to nutrition. We compared RNA-Seq profiles of G1 and G2 ISCs expressing CFP/YFP-Fucci using FACS sorting and RNA isolation from sorted G1 (CFP) and G2 (CFP+YFP) cells