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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">An Nkx2-5/Bmp2/Smad1 negative feedback loop controls second heart field progenitor specification and proliferation</title><author><name sortKey="Prall, Owen Wj" sort="Prall, Owen Wj" uniqKey="Prall O" first="Owen Wj" last="Prall">Owen Wj Prall</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Menon, Mary K" sort="Menon, Mary K" uniqKey="Menon M" first="Mary K" last="Menon">Mary K. Menon</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Solloway, Mark J" sort="Solloway, Mark J" uniqKey="Solloway M" first="Mark J" last="Solloway">Mark J. Solloway</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Watanabe, Yusuke" sort="Watanabe, Yusuke" uniqKey="Watanabe Y" first="Yusuke" last="Watanabe">Yusuke Watanabe</name><affiliation><nlm:aff id="A3"> Department of Developmental Biology, CNRS URA2578, Pasteur Institute, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Zaffran, Stephane" sort="Zaffran, Stephane" uniqKey="Zaffran S" first="Stéphane" last="Zaffran">Stéphane Zaffran</name><affiliation><nlm:aff id="A3"> Department of Developmental Biology, CNRS URA2578, Pasteur Institute, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bajolle, Fanny" sort="Bajolle, Fanny" uniqKey="Bajolle F" first="Fanny" last="Bajolle">Fanny Bajolle</name><affiliation><nlm:aff id="A3"> Department of Developmental Biology, CNRS URA2578, Pasteur Institute, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Biben, Christine" sort="Biben, Christine" uniqKey="Biben C" first="Christine" last="Biben">Christine Biben</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Mcbride, Jim J" sort="Mcbride, Jim J" uniqKey="Mcbride J" first="Jim J" last="Mcbride">Jim J. Mcbride</name><affiliation><nlm:aff id="A4"> Garvan Institute of Medical Research, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Robertson, Bronwyn R" sort="Robertson, Bronwyn R" uniqKey="Robertson B" first="Bronwyn R" last="Robertson">Bronwyn R. Robertson</name><affiliation><nlm:aff id="A5"> Ramaciotti Centre for Gene Function Analysis, University of New South Wales, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Chaulet, Herve" sort="Chaulet, Herve" uniqKey="Chaulet H" first="Hervé" last="Chaulet">Hervé Chaulet</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Stennard, Fiona A" sort="Stennard, Fiona A" uniqKey="Stennard F" first="Fiona A" last="Stennard">Fiona A. Stennard</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Wise, Natalie" sort="Wise, Natalie" uniqKey="Wise N" first="Natalie" last="Wise">Natalie Wise</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Schaft, Daniel" sort="Schaft, Daniel" uniqKey="Schaft D" first="Daniel" last="Schaft">Daniel Schaft</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Wolstein, Orit" sort="Wolstein, Orit" uniqKey="Wolstein O" first="Orit" last="Wolstein">Orit Wolstein</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Furtado, Milena B" sort="Furtado, Milena B" uniqKey="Furtado M" first="Milena B" last="Furtado">Milena B. Furtado</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Shiratori, Hidetaka" sort="Shiratori, Hidetaka" uniqKey="Shiratori H" first="Hidetaka" last="Shiratori">Hidetaka Shiratori</name><affiliation><nlm:aff id="A6"> Graduate School of Frontier Biosciences, Osaka University, Japan</nlm:aff></affiliation></author><author><name sortKey="Chien, Kenneth R" sort="Chien, Kenneth R" uniqKey="Chien K" first="Kenneth R" last="Chien">Kenneth R. Chien</name><affiliation><nlm:aff id="A7"> Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA</nlm:aff></affiliation></author><author><name sortKey="Hamada, Hiroshi" sort="Hamada, Hiroshi" uniqKey="Hamada H" first="Hiroshi" last="Hamada">Hiroshi Hamada</name><affiliation><nlm:aff id="A6"> Graduate School of Frontier Biosciences, Osaka University, Japan</nlm:aff></affiliation></author><author><name sortKey="Black, Brian L" sort="Black, Brian L" uniqKey="Black B" first="Brian L" last="Black">Brian L. Black</name><affiliation><nlm:aff id="A8"> Cardiovascular Research Institute, University of California, San Francisco, USA</nlm:aff></affiliation></author><author><name sortKey="Saga, Yumiko" sort="Saga, Yumiko" uniqKey="Saga Y" first="Yumiko" last="Saga">Yumiko Saga</name><affiliation><nlm:aff id="A9"> Division of Mammalian Development National Institute of Genetics, Mishima 411-8540, Japan</nlm:aff></affiliation></author><author><name sortKey="Robertson, Elizabeth J" sort="Robertson, Elizabeth J" uniqKey="Robertson E" first="Elizabeth J" last="Robertson">Elizabeth J. Robertson</name><affiliation><nlm:aff id="A10"> Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Buckingham, Margaret E" sort="Buckingham, Margaret E" uniqKey="Buckingham M" first="Margaret E" last="Buckingham">Margaret E. Buckingham</name><affiliation><nlm:aff id="A3"> Department of Developmental Biology, CNRS URA2578, Pasteur Institute, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Harvey, Richard P" sort="Harvey, Richard P" uniqKey="Harvey R" first="Richard P" last="Harvey">Richard P. Harvey</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Faculties of Life Sciences and Medicine, University of New South Wales, Kensington 2053, Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">17350578</idno><idno type="pmc">2092439</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2092439</idno><idno type="RBID">PMC:2092439</idno><idno type="doi">10.1016/j.cell.2007.01.042</idno><date when="2007">2007</date><idno type="wicri:Area/Pmc/Corpus">001D48</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001D48</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">An Nkx2-5/Bmp2/Smad1 negative feedback loop controls second heart field progenitor specification and proliferation</title><author><name sortKey="Prall, Owen Wj" sort="Prall, Owen Wj" uniqKey="Prall O" first="Owen Wj" last="Prall">Owen Wj Prall</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Menon, Mary K" sort="Menon, Mary K" uniqKey="Menon M" first="Mary K" last="Menon">Mary K. Menon</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Solloway, Mark J" sort="Solloway, Mark J" uniqKey="Solloway M" first="Mark J" last="Solloway">Mark J. Solloway</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Watanabe, Yusuke" sort="Watanabe, Yusuke" uniqKey="Watanabe Y" first="Yusuke" last="Watanabe">Yusuke Watanabe</name><affiliation><nlm:aff id="A3"> Department of Developmental Biology, CNRS URA2578, Pasteur Institute, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Zaffran, Stephane" sort="Zaffran, Stephane" uniqKey="Zaffran S" first="Stéphane" last="Zaffran">Stéphane Zaffran</name><affiliation><nlm:aff id="A3"> Department of Developmental Biology, CNRS URA2578, Pasteur Institute, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bajolle, Fanny" sort="Bajolle, Fanny" uniqKey="Bajolle F" first="Fanny" last="Bajolle">Fanny Bajolle</name><affiliation><nlm:aff id="A3"> Department of Developmental Biology, CNRS URA2578, Pasteur Institute, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Biben, Christine" sort="Biben, Christine" uniqKey="Biben C" first="Christine" last="Biben">Christine Biben</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Mcbride, Jim J" sort="Mcbride, Jim J" uniqKey="Mcbride J" first="Jim J" last="Mcbride">Jim J. Mcbride</name><affiliation><nlm:aff id="A4"> Garvan Institute of Medical Research, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Robertson, Bronwyn R" sort="Robertson, Bronwyn R" uniqKey="Robertson B" first="Bronwyn R" last="Robertson">Bronwyn R. Robertson</name><affiliation><nlm:aff id="A5"> Ramaciotti Centre for Gene Function Analysis, University of New South Wales, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Chaulet, Herve" sort="Chaulet, Herve" uniqKey="Chaulet H" first="Hervé" last="Chaulet">Hervé Chaulet</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Stennard, Fiona A" sort="Stennard, Fiona A" uniqKey="Stennard F" first="Fiona A" last="Stennard">Fiona A. Stennard</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Wise, Natalie" sort="Wise, Natalie" uniqKey="Wise N" first="Natalie" last="Wise">Natalie Wise</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Schaft, Daniel" sort="Schaft, Daniel" uniqKey="Schaft D" first="Daniel" last="Schaft">Daniel Schaft</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Wolstein, Orit" sort="Wolstein, Orit" uniqKey="Wolstein O" first="Orit" last="Wolstein">Orit Wolstein</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Furtado, Milena B" sort="Furtado, Milena B" uniqKey="Furtado M" first="Milena B" last="Furtado">Milena B. Furtado</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation></author><author><name sortKey="Shiratori, Hidetaka" sort="Shiratori, Hidetaka" uniqKey="Shiratori H" first="Hidetaka" last="Shiratori">Hidetaka Shiratori</name><affiliation><nlm:aff id="A6"> Graduate School of Frontier Biosciences, Osaka University, Japan</nlm:aff></affiliation></author><author><name sortKey="Chien, Kenneth R" sort="Chien, Kenneth R" uniqKey="Chien K" first="Kenneth R" last="Chien">Kenneth R. Chien</name><affiliation><nlm:aff id="A7"> Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA</nlm:aff></affiliation></author><author><name sortKey="Hamada, Hiroshi" sort="Hamada, Hiroshi" uniqKey="Hamada H" first="Hiroshi" last="Hamada">Hiroshi Hamada</name><affiliation><nlm:aff id="A6"> Graduate School of Frontier Biosciences, Osaka University, Japan</nlm:aff></affiliation></author><author><name sortKey="Black, Brian L" sort="Black, Brian L" uniqKey="Black B" first="Brian L" last="Black">Brian L. Black</name><affiliation><nlm:aff id="A8"> Cardiovascular Research Institute, University of California, San Francisco, USA</nlm:aff></affiliation></author><author><name sortKey="Saga, Yumiko" sort="Saga, Yumiko" uniqKey="Saga Y" first="Yumiko" last="Saga">Yumiko Saga</name><affiliation><nlm:aff id="A9"> Division of Mammalian Development National Institute of Genetics, Mishima 411-8540, Japan</nlm:aff></affiliation></author><author><name sortKey="Robertson, Elizabeth J" sort="Robertson, Elizabeth J" uniqKey="Robertson E" first="Elizabeth J" last="Robertson">Elizabeth J. Robertson</name><affiliation><nlm:aff id="A10"> Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Buckingham, Margaret E" sort="Buckingham, Margaret E" uniqKey="Buckingham M" first="Margaret E" last="Buckingham">Margaret E. Buckingham</name><affiliation><nlm:aff id="A3"> Department of Developmental Biology, CNRS URA2578, Pasteur Institute, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Harvey, Richard P" sort="Harvey, Richard P" uniqKey="Harvey R" first="Richard P" last="Harvey">Richard P. Harvey</name><affiliation><nlm:aff id="A1"> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Faculties of Life Sciences and Medicine, University of New South Wales, Kensington 2053, Australia</nlm:aff></affiliation></author></analytic><series><title level="j">Cell</title><idno type="ISSN">0092-8674</idno><idno type="eISSN">1097-4172</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p id="P3">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 <italic>Nkx2-5</italic> mutants, genes controlling cardiac specification (including <italic>Bmp2</italic>) and maintenance of the progenitor state were up-regulated, leading initially to progenitor over-specification, but subsequently to failed SHF proliferation and OFT truncation. In <italic>Smad1</italic> mutants, SHF proliferation and deployment to the OFT were increased, while <italic>Smad1</italic> deletion in <italic>Nkx2-5</italic> mutants rescued SHF proliferation and OFT development. In <italic>Nkx2-5</italic> hypomorphic mice, which recapitulate human congenital heart disease (CHD), OFT anomalies were also rescued by <italic>Smad1</italic> 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.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0413066</journal-id><journal-id journal-id-type="pubmed-jr-id">2830</journal-id><journal-id journal-id-type="nlm-ta">Cell</journal-id><journal-title>Cell</journal-title><issn pub-type="ppub">0092-8674</issn><issn pub-type="epub">1097-4172</issn></journal-meta><article-meta><article-id pub-id-type="pmid">17350578</article-id><article-id pub-id-type="pmc">2092439</article-id><article-id pub-id-type="doi">10.1016/j.cell.2007.01.042</article-id><article-id pub-id-type="manuscript">NIHMS29033</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>An Nkx2-5/Bmp2/Smad1 negative feedback loop controls second heart field progenitor specification and proliferation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Prall</surname><given-names>Owen WJ</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Menon</surname><given-names>Mary K</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Solloway</surname><given-names>Mark J</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Watanabe</surname><given-names>Yusuke</given-names></name><xref rid="A3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Zaffran</surname><given-names>Stéphane</given-names></name><xref rid="A3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Bajolle</surname><given-names>Fanny</given-names></name><xref rid="A3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Biben</surname><given-names>Christine</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>McBride</surname><given-names>Jim J</given-names></name><xref rid="A4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Robertson</surname><given-names>Bronwyn R</given-names></name><xref rid="A5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Chaulet</surname><given-names>Hervé</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Stennard</surname><given-names>Fiona A</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Wise</surname><given-names>Natalie</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Schaft</surname><given-names>Daniel</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Wolstein</surname><given-names>Orit</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Furtado</surname><given-names>Milena B</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Shiratori</surname><given-names>Hidetaka</given-names></name><xref rid="A6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Chien</surname><given-names>Kenneth R</given-names></name><xref rid="A7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Hamada</surname><given-names>Hiroshi</given-names></name><xref rid="A6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Black</surname><given-names>Brian L</given-names></name><xref rid="A8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Saga</surname><given-names>Yumiko</given-names></name><xref rid="A9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Robertson</surname><given-names>Elizabeth J</given-names></name><xref rid="A10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Buckingham</surname><given-names>Margaret E</given-names></name><xref rid="A3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Harvey</surname><given-names>Richard P</given-names></name><xref rid="A1" ref-type="aff">1</xref><xref rid="A2" ref-type="aff">2</xref><xref rid="FN1" ref-type="author-notes">*</xref></contrib></contrib-group><aff id="A1"><label>1</label> Victor Chang Cardiac Research Institute, Sydney 2010, Australia</aff><aff id="A2"><label>2</label> Faculties of Life Sciences and Medicine, University of New South Wales, Kensington 2053, Australia</aff><aff id="A3"><label>3</label> Department of Developmental Biology, CNRS URA2578, Pasteur Institute, Paris, France</aff><aff id="A4"><label>4</label> Garvan Institute of Medical Research, Sydney 2010, Australia</aff><aff id="A5"><label>5</label> Ramaciotti Centre for Gene Function Analysis, University of New South Wales, Sydney, Australia</aff><aff id="A6"><label>6</label> Graduate School of Frontier Biosciences, Osaka University, Japan</aff><aff id="A7"><label>7</label> Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA</aff><aff id="A8"><label>8</label> Cardiovascular Research Institute, University of California, San Francisco, USA</aff><aff id="A9"><label>9</label> Division of Mammalian Development National Institute of Genetics, Mishima 411-8540, Japan</aff><aff id="A10"><label>10</label> Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK</aff><author-notes><corresp id="FN1">* Corresponding author: <email>r.harvey@victorchang.unsw.edu.au</email>, (tel) +61 2 9295 8520, (fax) +61 2 9295 8528</corresp></author-notes><pub-date pub-type="nihms-submitted"><day>13</day><month>11</month><year>2007</year></pub-date><pub-date pub-type="ppub"><day>9</day><month>3</month><year>2007</year></pub-date><pub-date pub-type="pmc-release"><day>9</day><month>3</month><year>2008</year></pub-date><volume>128</volume><issue>5</issue><fpage>947</fpage><lpage>959</lpage><abstract><title>Summary</title><p id="P3">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 <italic>Nkx2-5</italic> mutants, genes controlling cardiac specification (including <italic>Bmp2</italic>) and maintenance of the progenitor state were up-regulated, leading initially to progenitor over-specification, but subsequently to failed SHF proliferation and OFT truncation. In <italic>Smad1</italic> mutants, SHF proliferation and deployment to the OFT were increased, while <italic>Smad1</italic> deletion in <italic>Nkx2-5</italic> mutants rescued SHF proliferation and OFT development. In <italic>Nkx2-5</italic> hypomorphic mice, which recapitulate human congenital heart disease (CHD), OFT anomalies were also rescued by <italic>Smad1</italic> 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.</p></abstract><contract-num rid="HD1">R21 HD047858-01</contract-num><contract-sponsor id="HD1">National Institute of Child Health & Human Development : NICHD</contract-sponsor></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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