A microRNA forms feedback loops with protein factors and provides robustness to developmental decisions in the Drosophila eye.

摘要

In the process of development of a multicellular organism, cells must make stable, binary fate decisions in response to intercellular signaling. A critical question is how weak or transient activation of signaling pathways achieves a robust and long-term switch in gene expression, and thus determines cell fate. I report that a microRNA is part of a mechanism that provides robustness to developmental decisions in Drosophila. Expression of the microRNA miR-7 is turned on in cells as they begin to differentiate into photoreceptors. This is dependent on EGF Receptor (EGFR) signaling that triggers degradation of the ETS transcription factor Yan. In non-stimulated cells, stabilized Yan represses miR-7 transcription. In turn, miR-7 RNA represses Yan protein expression in photoreceptors, by binding to complementary sequences within its mRNA 3'UTR. I propose that reciprocal negative feedback regulation between Yan and miR-7 ensures their mutually exclusive expression, with Yan in progenitor cells and miR-7 in photoreceptor cells. Expression is switched when EGFR signaling transiently triggers Yan degradation. The long-term depletion of Yan from differentiating cells is critical since it inhibits transcription of multiple cell-specific genes. Thus, a feedback loop involving miR-7 reinforces a developmental decision. Furthermore, I provide evidence that miR-7 may participate in a different feedback loop together with the Notch signaling pathway and the proneural gene atonal. I propose that Atonal activates the expression of miR-7, which in turn represses the expression of Notch target genes, encoding a group of transcriptional repressors that repress the expression of atonal . Thus a positive feedback loop for the expression of atonal would help to stabilize distinctive expression patterns of atonal and its repressors, and provide robustness to cell fate commitment. Altogether, these feedback loops involving miR-7 and protein factors help to explain how signal transduction activity can robustly generate a stable change in gene expression patterns in the Drosophila eye.