TY - JOUR
T1 - Brat Promotes Stem Cell Differentiation via Control of a Bistable Switch that Restricts BMP Signaling
AU - Harris, Robin E.
AU - Pargett, Michael
AU - Sutcliffe, Catherine
AU - Umulis, David
AU - Ashe, Hilary L.
N1 - Funding Information:
We thank R. Wharton, B. Edgar, T. Tabata, D. McKearin, J. Knoblich, R. Lehmann, S. Luschnig, R Baines, and the Bloomington Stock Center for fly stocks and antibodies, and Mark Ashe for advice and critical evaluation of the manuscript. This work was funded by a Wellcome Trust project grant (083211/Z/07/Z) to H.L.A. and a BBSRC studentship to R.E.H./H.L.A. D.U. and M.P. were supported by a grant from the Showalter Trust.
PY - 2011/1/18
Y1 - 2011/1/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78651438047&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78651438047&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2010.11.019
DO - 10.1016/j.devcel.2010.11.019
M3 - Article
C2 - 21238926
AN - SCOPUS:78651438047
SN - 1534-5807
VL - 20
SP - 72
EP - 83
JO - Developmental Cell
JF - Developmental Cell
IS - 1
ER -