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An Nkx2-5/Bmp2/Smad1 negative feedback loop controls second heart field progenitor specification and proliferation

Citation

Prall, OW and Menon, Mk and Solloway, MJ and Watanabe, Y and Zaffran, S and Bajolle, F and Biben, C and McBride, JJ and Roberston, BR and Chaulet, H and Stennard, FA and Wise, N and Schaft, D and Wolstein, O and Furtado, MB and Shiratori, H and Chien, KR and Hamada, H and Black, BL and Saga, Y and Robertson, EJ and Buckingham, ME and Harvey, RP, An Nkx2-5/Bmp2/Smad1 negative feedback loop controls second heart field progenitor specification and proliferation, Cell, 128, (5) pp. 947-959. ISSN 0092-8674 (2007) [Refereed Article]

Copyright Statement

Copyright 2007 Elsevier

DOI: doi:10.1016/j.cell.2007.01.042

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.

Item Details

Item Type:Refereed Article
Keywords:mammalian cardiac development
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Developmental Genetics (incl. Sex Determination)
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Environmental Sciences
Author:Stennard, FA (Dr Fiona Stennard)
ID Code:99853
Year Published:2007
Web of Science® Times Cited:279
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-04-13
Last Modified:2016-12-06
Downloads:91 View Download Statistics

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