Preaxial polydactyly: interactions among ETV, TWIST1 and HAND2 control anterior-posterior patterning of the limb.
Preaxial polydactyly (PPD) is a common limb-associated birth defect characterized by extra digit(s) in the anterior autopod. It often results from ectopic sonic hedgehog (Shh) expression in the anterior limb bud. Although several transcription factors are known to restrict Shh expression to the posterior limb bud, how they function together remains unclear. Here we provide evidence from mouse conditional knockout limb buds that the bHLH family transcription factor gene Twist1 is required to inhibit Shh expression in the anterior limb bud mesenchyme. More importantly, we uncovered genetic synergism between Twist1 and the ETS family transcription factor genes Etv4 and Etv5 (collectively Etv), which also inhibit Shh expression. Biochemical data suggest that this genetic interaction is a result of direct association between TWIST1 and ETV proteins. Previous studies have shown that TWIST1 functions by forming homodimers or heterodimers with other bHLH factors including HAND2, a key positive regulator of Shh expression. We found that the PPD phenotype observed in Etv mutants is suppressed by a mutation in Hand2, indicative of genetic antagonism. Furthermore, overexpression of ETV proteins influences the dimerization of these bHLH factors. Together, our data suggest that through biochemical interactions, the Shh expression regulators ETV, TWIST1 and HAND2 attain a precise balance to establish anterior-posterior patterning of the limb.
Zhang
Zhen
Z
Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.
Sui
Pengfei
P
Dong
Aiwu
A
Hassell
John
J
Cserjesi
Peter
P
Chen
You-Tzung
YT
Behringer
Richard R
RR
Sun
Xin
X
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015153:Blotting, Western; D019521:Body Patterning / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D053823:Hedgehog Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D017689:Polydactyly / Q000196:embryology*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D034941:Upper Extremity / Q000196:embryology*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D009687:Nuclear Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C540571:Etv4 protein, mouse; C513242:Etv5 protein, mouse; C498766:Hand2 protein, mouse; C465570:Shh protein, mouse; C067250:Twist1 protein, mouse
Mol Cell Biol. 2004 Nov;24(22):9835-47
15509787
Mech Dev. 2001 Oct;108(1-2):191-5
11578874
Dev Biol. 2002 Aug 1;248(1):143-56
12142027
J Biol Chem. 2002 Mar 15;277(11):9118-26
11756408
Dev Cell. 2009 Apr;16(4):607-13
19386269
Development. 2000 May;127(10):2133-42
10769237
Genesis. 2002 Jun;33(2):77-80
12112875
Mech Dev. 1996 May;56(1-2):93-101
8798150
Genes Dev. 2002 Feb 15;16(4):421-6
11850405
Mech Dev. 2002 Jun;114(1-2):51-9
12175489
Curr Opin Genet Dev. 2006 Aug;16(4):426-32
16806898
Dev Biol. 2008 Aug 1;320(1):131-9
18539270
Development. 2002 Jul;129(13):3077-88
12070084
Dev Biol. 2001 Aug 15;236(2):421-35
11476582
Nat Genet. 2005 Apr;37(4):373-81
15735646
Nat Rev Mol Cell Biol. 2001 Nov;2(11):827-37
11715049
Genesis. 2007 Sep;45(9):588-92
17868088
Genes Dev. 1995 Mar 15;9(6):686-99
7729687
Dev Dyn. 2006 May;235(5):1345-57
16502419
Curr Opin Genet Dev. 2007 Aug;17(4):359-66
17644373
Dev Biol. 1997 Aug 15;188(2):235-47
9268572
Development. 2005 Feb;132(4):797-803
15677727
Am J Med Genet A. 2007 Jan 1;143A(1):27-32
17152067
Development. 1998 Jul;125(14):2711-21
9636085
Development. 1997 Oct;124(20):3999-4008
9374397
Dev Biol. 2007 Jul 1;307(1):114-26
17531968
Hum Mol Genet. 2003 Jul 15;12(14):1725-35
12837695
Mech Dev. 1997 Mar;62(2):175-82
9152009
Dev Cell. 2009 Apr;16(4):600-6
19386268
Development. 2005 Sep;132(17):3859-71
16049111
Development. 2006 Jun;133(11):2263-73
16672333
Genes Dev. 2008 Oct 1;22(19):2651-63
18832070
Mech Dev. 2001 Jan;100(1):45-58
11118883
Dev Dyn. 2005 Feb;232(2):345-8
15637698
Development. 2004 Aug;131(16):3885-96
15253939
Int J Dev Biol. 2005;49(4):443-8
15968591
Nat Rev Genet. 2009 Dec;10(12):845-58
19920852
Hum Mol Genet. 1998 Jun;7(6):945-57
9580658
Int J Dev Biol. 2002;46(7):877-81
12455624
Dev Biol. 1997 Feb 1;182(1):42-51
9073443
Nature. 2006 Oct 26;443(7114):985-8
17066034
Mamm Genome. 2004 Jan;15(1):23-34
14727139
PLoS Genet. 2010 Apr 08;6(4):e1000901
20386744
Cell. 1997 Jul 25;90(2):247-55
9244299
Cell. 2004 Jun 25;117(7):927-39
15210113
Dev Dyn. 1995 Nov;204(3):316-22
8573722
Development. 2003 May;130(10):2263-73
12668638
Int J Cancer. 1997 Mar 4;70(5):590-7
9052761
Development. 2004 May;131(10):2339-47
15102708
Neuron. 2002 Aug 29;35(5):877-92
12372283
Hum Mol Genet. 2008 Aug 15;17(16):2417-23
18463159
Dev Cell. 2004 Mar;6(3):423-35
15030764
J Biol Chem. 2007 Sep 14;282(37):27536-27546
17652084
Cell. 2001 Jun 1;105(5):599-612
11389830
Development. 2000 Jun;127(11):2461-70
10804186