Brat promotes stem cell differentiation via control of a bistable switch that restricts BMP signaling.
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.
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Robin E
RE
Harris
Michael
M
Pargett
Catherine
C
Sutcliffe
David
D
Umulis
Hilary L
HL
Ashe
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism; D005260:Female; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D012097:Repressor Proteins; C412783:brat protein, Drosophila
Curr Biol. 2007 Mar 20;17(6):533-8
17320391
Curr Biol. 2004 Feb 17;14(4):314-21
14972682
Structure. 2008 Apr;16(4):549-57
18328718
Development. 2004 Mar;131(6):1353-64
14973291
Development. 2004 May;131(9):1881-90
15105369
Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4487-92
16537387
Development. 2009 Nov;136(21):3627-35
19793889
Oncogene. 2000 Aug 3;19(33):3706-16
10949924
Cell. 2004 Apr 2;117(1):117-29
15066287
Cell. 2006 Mar 24;124(6):1241-53
16564014
Development. 1997 Sep;124(18):3651-62
9342057
Nature. 1997 Oct 9;389(6651):627-31
9335506
Curr Biol. 2005 Jan 26;15(2):179-84
15668176
Mol Cell Biol. 1999 Apr;19(4):2505-14
10082516
Cell. 1998 Jul 24;94(2):251-60
9695953
J Cell Biol. 2008 Feb 25;180(4):721-8
18283115
Genes Dev. 2009 Dec 1;23(23):2742-52
19952109
Sci Signal. 2010 Jul 27;3(132):ra57
20664066
J Neurosci. 2008 Feb 27;28(9):2099-109
18305244
EMBO J. 2010 May 19;29(10):1688-98
20400939
Development. 2007 Apr;134(8):1519-27
17360772
Nature. 2008 Jul 10;454(7201):241-5
18528333
BMC Cancer. 2009 Feb 27;9:71
19250537
Curr Biol. 2005 Jan 26;15(2):171-8
15668175
Development. 2000 Dec;127(23):5225-32
11060247
Curr Biol. 2003 Oct 14;13(20):1786-91
14561403
Nat Cell Biol. 2009 Dec;11(12):1411-20
19898466
Nature. 2004 Apr 1;428(6982):564-9
15024390
Nat Cell Biol. 2005 Mar;7(3):295-302
15723055
Development. 2003 Mar;130(6):1159-70
12571107
Development. 2002 Jan;129(2):399-407
11807032
Dev Cell. 2004 Aug;7(2):229-40
15296719
Genetics. 2005 Aug;170(4):1677-89
15937125
Development. 2009 Mar;136(6):995-1006
19211674
Genes Dev. 2001 Mar 15;15(6):762-73
11274060
Curr Biol. 2006 Oct 24;16(20):2035-41
17055983
Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9304-9
19470484
Development. 2007 Dec;134(23):4265-72
17993467
Development. 2006 Jul;133(14):2639-48
16774999
Science. 2000 Oct 13;290(5490):328-30
11030649
Genes Dev. 1999 Oct 15;13(20):2704-12
10541556
Dev Cell. 2009 Jul;17(1):123-33
19619497
Curr Biol. 2007 Mar 20;17(6):539-44
17306537
Development. 1998 Feb;125(4):679-90
9435288
Nat Cell Biol. 1999 Nov;1(7):431-7
10559987
Development. 2005 Dec;132(24):5365-74
16280348
J Biol Chem. 2010 Feb 12;285(7):4741-6
20018853
Cell Res. 2007 Jan;17(1):15-25
17199109
Science. 2004 Mar 26;303(5666):2016-9
14976263
Development. 2008 Feb;135(3):533-40
18171682
Genetics. 2007 Mar;175(3):1505-31
17194782
Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12016-21
18687884
Cell Stem Cell. 2008 Jan 10;2(1):39-49
18371420
Nature. 2008 Sep 4;455(7209):72-7
18701888
Cell. 2009 Mar 6;136(5):913-25
19269368