Brat Promotes Stem Cell Differentiation via Control of a Bistable Switch that Restricts BMP Signaling

Robin E. Harris, Michael Pargett, Catherine Sutcliffe, David Umulis, Hilary L. Ashe

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Drosophila ovarian germline stem cells (GSCs) are maintained by Dpp signaling and the Pumilio (Pum) and Nanos (Nos) translational repressors. Upon division, Dpp signaling is extinguished, and Nos is downregulated in one daughter cell, causing it to switch to a differentiating cystoblast (CB). However, downstream effectors of Pum-Nos remain unknown, and how CBs lose their responsiveness to Dpp is unclear. Here, we identify Brain Tumor (Brat) as a potent differentiation factor and target of Pum-Nos regulation. Brat is excluded from GSCs by Pum-Nos but functions with Pum in CBs to translationally repress distinct targets, including the Mad and dMyc mRNAs. Regulation of both targets simultaneously lowers cellular responsiveness to Dpp signaling, forcing the cell to become refractory to the self-renewal signal. Mathematical modeling elucidates bistability of cell fate in the Brat-mediated system, revealing how autoregulation of GSC number can arise from Brat coupling extracellular Dpp regulation to intracellular interpretation. © 2011 Elsevier Inc.
    Original languageEnglish
    Pages (from-to)72-83
    Number of pages11
    JournalDevelopmental cell
    Volume20
    Issue number1
    DOIs
    Publication statusPublished - 18 Jan 2011

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