title: Maternal Groucho and bHLH repressors amplify the dose-sensitive X chromosome signal in Drosophila sex determination.
abstract: In Drosophila, XX embryos are fated to develop as females, and XY embryos as males, because the diplo-X dose of four X-linked signal element genes, XSEs, activates the Sex-lethal establishment promoter, SxlPe, whereas the haplo-X XSE dose leaves SxlPe off. The threshold response of SxlPe to XSE concentrations depends in part on the bHLH repressor, Deadpan, present in equal amounts in XX and XY embryos. We identified canonical and non-canonical DNA-binding sites for Dpn at SxlPe and found that cis-acting mutations in the Dpn-binding sites caused stronger and earlier Sxl expression than did deletion of dpn implicating other bHLH repressors in Sxl regulation. Maternal Hey encodes one such bHLH regulator but the E(spl) locus does not. Elimination of the maternal corepressor Groucho also caused strong ectopic Sxl expression in XY, and premature Sxl activation in XX embryos, but Sxl was still expressed differently in the sexes. Our findings suggest that Groucho and associated maternal and zygotic bHLH repressors define the threshold XSE concentrations needed to activate SxlPe and that they participate directly in sex signal amplification. We present a model in which the XSE signal is amplified by a feedback mechanism that interferes with Gro-mediated repression in XX, but not XY embryos.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Elena
authors.initials: E
authors.lastname: Kozhina
authors.forename: Sharvani
authors.initials: S
authors.lastname: Mahadevaraju
authors.forename: Dun
authors.initials: D
authors.lastname: Yang
authors.forename: Frank W
authors.initials: FW
authors.lastname: Avila
authors.forename: James W
authors.initials: JW
authors.lastname: Erickson
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D004268:DNA-Binding Proteins; D004303:Dosage Compensation, Genetic; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D019849:Sex Determination Processes; D013997:Time Factors; D019076:Transgenes; D014960:X Chromosome / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C120390:Hey protein, Drosophila; C067777:Sxl protein, Drosophila; C091023:gro protein, Drosophila; C078020:Dpn protein, Drosophila
references.citation: Mol Cell Biol. 2008 Apr;28(8):2792-802
references.pmid: 18285466
references.citation: Development. 2007 Apr;134(7):1243-51
references.pmid: 17329370
references.citation: Science. 2003 Dec 5;302(5651):1727-36
references.pmid: 14605208
references.citation: Dev Cell. 2003 Aug;5(2):285-94
references.pmid: 12919679
references.citation: Science. 1999 Apr 23;284(5414):606-9
references.pmid: 10213677
references.citation: Development. 2006 May;133(10):1967-77
references.pmid: 16624855
references.citation: Nucleic Acids Res. 1995 Sep 11;23(17):3441-8
references.pmid: 7567454
references.citation: Mol Cell Biochem. 2005 Jun;274(1-2):133-9
references.pmid: 16342413
references.citation: Cell. 1992 Mar 6;68(5):933-43
references.pmid: 1547493
references.citation: Genetics. 1996 Dec;144(4):1673-9
references.pmid: 8978054
references.citation: Nature. 2003 Dec 18;426(6968):849-53
references.pmid: 14685241
references.citation: Genome Biol. 2002;3(12):RESEARCH0088
references.pmid: 12537577
references.citation: Biol Rev Camb Philos Soc. 2003 Feb;78(1):149-70
references.pmid: 12620064
references.citation: Mech Dev. 1999 Jul;85(1-2):173-7
references.pmid: 10415358
references.citation: Genes Dev. 2001 Nov 1;15(21):2786-96
references.pmid: 11691830
references.citation: Development. 2000 Feb;127(4):667-77
references.pmid: 10648226
references.citation: Genes Dev. 1994 Nov 15;8(22):2743-55
references.pmid: 7958930
references.citation: Mol Cell Biol. 1999 Mar;19(3):2080-7
references.pmid: 10022895
references.citation: Genes Dev. 2002 May 15;16(10):1167-81
references.pmid: 12023297
references.citation: Cell. 1991 Apr 19;65(2):229-39
references.pmid: 2015624
references.citation: Cell. 1990 Dec 21;63(6):1179-91
references.pmid: 2124516
references.citation: Genes Dev. 1997 Nov 15;11(22):3072-82
references.pmid: 9367988
references.citation: J Cell Physiol. 2003 Mar;194(3):237-55
references.pmid: 12548545
references.citation: PLoS Biol. 2007 Dec;5(12):e332
references.pmid: 18162044
references.citation: Cell. 1989 Feb 24;56(4):573-83
references.pmid: 2563673
references.citation: Mol Cell Biol. 2000 Jan;20(2):429-40
references.pmid: 10611221
references.citation: Annu Rev Biochem. 2007;76:75-100
references.pmid: 17362198
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):4960-5
references.pmid: 15793007
references.citation: Genes Dev. 1998 Jul 1;12(13):1931-40
references.pmid: 9649497
references.citation: Genetics. 1984 Jun;107(2):231-77
references.pmid: 6735170
references.citation: Mol Cell Biol. 2001 Mar;21(5):1581-92
references.pmid: 11238895
references.citation: Cell. 1991 Oct 18;67(2):303-10
references.pmid: 1680567
references.citation: Nucleic Acids Res. 2007;35(14):4583-96
references.pmid: 17586813
references.citation: Genesis. 2004 Jun;39(2):105-14
references.pmid: 15170696
references.citation: Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):535-40
references.pmid: 9892668
references.citation: Development. 1998 Aug;125(16):3259-68
references.pmid: 9671597
references.citation: EMBO J. 1998 Apr 1;17(7):2067-78
references.pmid: 9524128
references.citation: EMBO J. 1997 May 15;16(10):2883-91
references.pmid: 9184232
references.citation: Genes Dev. 1994 Feb 15;8(4):440-52
references.pmid: 7510257
references.citation: Biochemistry. 1999 Apr 20;38(16):5138-46
references.pmid: 10213619
references.citation: Cell. 2007 Jul 13;130(1):153-64
references.pmid: 17632062
references.citation: Genes Dev. 1994 Nov 15;8(22):2729-42
references.pmid: 7958929
references.citation: Mol Cell Biol. 2001 Sep;21(17):6080-9
references.pmid: 11486045
references.citation: Mol Cell Biol. 1995 Dec;15(12):6923-31
references.pmid: 8524259
references.citation: Genetics. 2003 Dec;165(4):2007-27
references.pmid: 14704182
references.citation: Annu Rev Genet. 1996;30:637-702
references.pmid: 8982468
references.citation: Nature. 1989 Jul 20;340(6230):245-6
references.pmid: 2547163
references.citation: PLoS Biol. 2004 Jul;2(7):E178
references.pmid: 15252443
references.citation: Mol Cell. 2007 Oct 26;28(2):291-303
references.pmid: 17964267
references.citation: Mol Cell Biol. 1995 Feb;15(2):904-17
references.pmid: 7823955
references.citation: Genetics. 1988 Aug;119(4):829-62
references.pmid: 3137120
references.citation: PLoS Biol. 2007 May;5(5):e117
references.pmid: 17456005
references.citation: EMBO Rep. 2008 Jan;9(1):76-83
references.pmid: 18034187
references.citation: Mol Cell Biol. 1997 Sep;17(9):5581-7
references.pmid: 9271433
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10436-41
references.pmid: 10973473
references.citation: Mol Cell Biol. 1996 Jun;16(6):2670-7
references.pmid: 8649374
references.citation: Nat Genet. 2007 Jun;39(6):715-20
references.pmid: 17534367
references.citation: Curr Biol. 2007 Apr 3;17(7):643-8
references.pmid: 17363251
references.citation: Mol Gen Genet. 1995 Jul 28;248(2):182-9
references.pmid: 7651341
references.citation: Oncogene. 2001 Dec 20;20(58):8342-57
references.pmid: 11840327
references.citation: Genetics. 2003 Mar;163(3):931-7
references.pmid: 12663533
references.citation: Gene. 2000 May 16;249(1-2):1-16
references.pmid: 10831834
references.citation: Trends Cell Biol. 2007 Jul;17(7):353-61
references.pmid: 17643306
references.citation: Genes Dev. 1996 May 15;10(10):1247-59
references.pmid: 8675011
references.citation: Biochem Biophys Res Commun. 1999 Jul 5;260(2):459-65
references.pmid: 10403790
references.citation: Mol Cell. 2006 Jun 9;22(5):645-55
references.pmid: 16762837
references.citation: Genome Res. 2001 May;11(5):754-70
references.pmid: 11337472
references.citation: Trends Genet. 1993 Nov;9(11):385-90
references.pmid: 8310535
references.citation: Development. 2003 Feb;130(3):463-71
references.pmid: 12490553
references.citation: Methods Cell Biol. 1994;44:445-87
references.pmid: 7707967
references.citation: Genetics. 2003 Nov;165(3):1355-84
references.pmid: 14668388
references.citation: Cell. 1994 Dec 2;79(5):805-15
references.pmid: 8001118
references.citation: Oncogene. 2001 Dec 20;20(58):8299-307
references.pmid: 11840322
references.citation: J Mol Biol. 1999 Feb 19;286(2):315-25
references.pmid: 9973553
references.citation: Cell. 1992 Sep 18;70(6):911-22
references.pmid: 1525829
references.citation: Genes Dev. 1993 Sep;7(9):1688-702
references.pmid: 8370520
references.citation: Genetics. 1995 Dec;141(4):1451-71
references.pmid: 8601486