David Foronda1, Ruifen Weng1, Pushpa Verma1, Ya-Wen Chen1, and Stephen M. Cohen1,2
1 Institute of Molecular and Cell Biology, Singapore 138673, Singapore
2 Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
Published in Genes & Development on 1 November 2014.
Homeostasis of the intestine is maintained by dynamic regulation of a pool of intestinal stem cells. The balance between stem cell self-renewal and differentiation is regulated by the Notch and insulin signaling pathways. Dependence on the insulin pathway places the stem cell pool under nutritional control, allowing gut homeostasis to adapt to environmental conditions. Here we present evidence that miR-305 is required for adaptive homeostasis of the gut. miR-305 regulates the Notch and insulin pathways in the intestinal stem cells. Notably, miR-305 expression in the stem cells is itself under nutritional control via the insulin pathway. This link places regulation of Notch pathway activity under nutritional control. These findings provide a mechanism through which the
insulin pathway controls the balance between stem cell self-renewal and differentiation that is required for adaptive homeostasis in the gut in response to changing environmental conditions.
miR-305 targets in ISC self-renewal
and differentiation. (A) Schematic representation
of the intestinal epithelium. EB, EC, and
EE cells. (B) Predicted miR-305 targets in signaling
pathways involved in ISC self-renewal and differentiation.
Figure Legend: miR-305 acts in ISCs. (A–B) Images of posterior midguts expressing a miR-305 sensor transgene (green). Samples were labeled with anti-Dl to visualize ISCs (red) and with DAPI (blue).
(A) Normal control, surface view. ISCs and EB cells are diploid and have small nuclei. (Arrows) A Dl-expressing ISC; (arrowheads) adjacent EBs. miR-305 sensor GFP levels were lower in the nuclei of the small cells. This difference disappeared in the miR-305 mutant background (Supplemental Fig. S2).
(B) Optical cross-section showing an adjacent pair of basally located ISCs and EB cells. miR-305 sensor GFP levels were similar to background GFP levels in the ISCs but were detectable above background in the EB cell.
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