Several types of stem and progenitor cells in animals switch between the quiescent and activated states in response to shifts in dietary conditions. Although defects in this coordination have been proposed to contribute to diseases, much of its mechanism remains unknown. Under the nutritionally poor conditions, stem and progenitor cells in newly hatched C. elegans L1 larvae can maintain quiescence over a week, and can be reproducibly reactivated by feeding food. We have previously shown that upregulation of miR-235 maintains the quiescence in neural progenitors, P cells under nutritionally deprived conditions, and the insulin/IGF signaling (IIS) pathway downregulates the microRNA to reactivate these cells upon feeding (Nature 2013). Since both the IIS pathway and miR-235 act in the hypodermis outside P cells, we hypothesized that the miRNA suppresses an intercellular signaling pathway that links these two lineages.
Among predicted miR-235 targets, a hedgehog-related gene grl-7 showed ectopic upregulation in starved mir-235 null mutants. Furthermore, overexpression of grl-7 in starved, wild type L1 larvae can reactivate quiescent P cells. Studies using reporter genes suggest that grl-7 is a bona fide miR-235 target. We also identified a patched related (PTR)/patched-domain containing (PTCHD) gene that is expressed in P cells and required for maintaining their quiescence. Although human PTCHD1 has been shown to be related to autism, little is known about its physiological roles. Thus, our findings suggest a novel role of the hedgehog- PTCHD signaling in coupling reactivation of quescent neural progenitors to the dietary environment.
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