title: An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation.
abstract: During heart development the second heart field (SHF) provides progenitor cells for most cardiomyocytes and expresses the homeodomain factor Nkx2-5. We now show that feedback repression of Bmp2/Smad1 signaling by Nkx2-5 critically regulates SHF proliferation and outflow tract (OFT) morphology. In the cardiac fields of Nkx2-5 mutants, genes controlling cardiac specification (including Bmp2) and maintenance of the progenitor state were upregulated, leading initially to progenitor overspecification, but subsequently to failed SHF proliferation and OFT truncation. In Smad1 mutants, SHF proliferation and deployment to the OFT were increased, while Smad1 deletion in Nkx2-5 mutants rescued SHF proliferation and OFT development. In Nkx2-5 hypomorphic mice, which recapitulate human congenital heart disease (CHD), OFT anomalies were also rescued by Smad1 deletion. Our findings demonstrate that Nkx2-5 orchestrates the transition between periods of cardiac induction, progenitor proliferation, and OFT morphogenesis via a Smad1-dependent negative feedback loop, which may be a frequent molecular target in CHD.
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney 2010, Australia.
authors.forename: Owen W J
authors.initials: OW
authors.lastname: Prall
authors.forename: Mary K
authors.initials: MK
authors.lastname: Menon
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Solloway
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Stéphane
authors.initials: S
authors.lastname: Zaffran
authors.forename: Fanny
authors.initials: F
authors.lastname: Bajolle
authors.forename: Christine
authors.initials: C
authors.lastname: Biben
authors.forename: Jim J
authors.initials: JJ
authors.lastname: McBride
authors.forename: Bronwyn R
authors.initials: BR
authors.lastname: Robertson
authors.forename: Hervé
authors.initials: H
authors.lastname: Chaulet
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Stennard
authors.forename: Natalie
authors.initials: N
authors.lastname: Wise
authors.forename: Daniel
authors.initials: D
authors.lastname: Schaft
authors.forename: Orit
authors.initials: O
authors.lastname: Wolstein
authors.forename: Milena B
authors.initials: MB
authors.lastname: Furtado
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Shiratori
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamada
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Robertson
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Buckingham
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D018076:DNA, Complementary; D004622:Embryo, Mammalian; D025461:Feedback, Physiological; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051898:Smad1 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D018076:DNA, Complementary; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C063843:insulin gene enhancer binding protein Isl-1