Li and Carthew set out to address how a transient signal can produce a long-lasting effect and used differentiation of the fly eye as a model. The fly eye is composed of ommatidium, and the first cell to differentiate is the R8 cell, which then signals to the neighboring cells to form seven photoreceptor (R7) cells, and then finally four nonneuronal cone cells are recruited. R8 cells release the ligand (Spitz) for the epidermal growth factor receptor (EGFR) of the R7 progenitor cells, which triggers the phosphorylation of the transcriptional repressor Yan by extracellular signal-regulated kinase (ERK), leading to degradation of Yan and alleviation of gene repression. Li and Carthew showed that the microRNA miR-7 was present in the differentiating R7 cells and that overexpression of miR-7 increased the number of R7 cells. The abundance of Yan was also decreased in progenitor cells overexpressing miR-7. In cells with a constitutively active EGFR, miR-7 abundance was increased, and this appeared to be mediated by Yan. In cells expressing a Yan loss-of-function mutant or expressing a nonphosphorylatable form of Yan, miR-7 abundance was increased compared with that in wild-type cells. As with other targets of Yan, expression of miR-7 was increased by overexpression of the transcription factor Pointed-P1, which competes with Yan at target genes. Thus, in the eye, in cells in which EGFR is not activated, Yan represses gene expression, including the production of miR-7. The EGFR signal results in degradation of Yan, which alleviates repression of miR-7, which in turn further represses Yan production. This reciprocal feedback loop sets the stage for proper differentiation.
X. Li, R. W. Carthew, A microRNA mediates EGF receptor signaling and promotes photoreceptor differentiation in the Drosophila eye. Cell 123, 1267-1277 (2005). [PubMed]