Differentiation of mammalian cells is viewed as a hierarchical feed-forward process, in which multipotent progenitors are fate-restricted by positional cues. Accordingly, Neurogenin3--positive (Neurog3+) endocrine progenitors differentiate into insulin-producing cells in the pancreas, but not in the gut. Here we show that somatic ablation of Foxo1 in Neurog3 + enteroendocrine progenitors results in expanded pool of Neurog3 + progenitors, and hormone-producing populations, including additional fates: glucagon-producing cells and insulin-positive (Ins+) cells. Enteric Ins+ cells express genes required for glucose-sensing, glucose metabolism, insulin biosynthesis, and processing, and secrete insulin and C-peptide in response to glucose. Moreover, acidethanol extracts from gut of Neurog3-Foxo1flox/flox mice lower blood glucose when injected into newborn mice. And unlike pancreatic beta-cells, gut Ins+ cells regenerate following ablation by the beta-cell toxin, streptozotocin. The data indicate that Foxo1 is a regulator of cell fate restriction in enteroendocrine progenitors, and is required to suppress the insulin-producing cell fate in the gut. Our results provide impetus to develop Foxo1 inhibition in gut endocrine cells as a mean to restore insulin production in insulin--dependent diabetes.
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