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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,9,9]]},"abstract":"<jats:p>\n                    Cardiogenesis relies on the integrated interplay between cardiac transcription factors and signaling pathways. Here, we uncover a role for type IIA procollagen (IIA), an extracellular matrix (ECM) protein encoded by an alternatively spliced\n                    <jats:italic toggle=\"yes\">Col2a1<\/jats:italic>\n                    transcript, encoding a N-terminal cysteine-rich domain, as a critical regulator in a cardiac gene regulatory feedback loop. The cysteine-rich domain of IIA protein was previously reported to interact with bone morphogenetic proteins (BMPs) and transforming growth factors-beta (TGF\u03b2) in in vitro binding assays and acts as a BMP antagonist in amphibian embryo assays. We show that the\n                    <jats:italic toggle=\"yes\">Col2a1<\/jats:italic>\n                    gene in mice is activated in the developing heart by core cardiogenic factors (NKX2-5, GATA4, MEF2, and SRF) via cis-regulatory enhancer elements. IIA loss (\u0394IIA) in mice results in depletion of Isl1- and Nkx2-5-expressing progenitors, causing outflow tract defects resembling disrupted BMP\/TGF\u03b2-SMAD signaling, alongside reduced nuclear pSMAD1\/5\/8 in cardiac tissues. Compound\n                    <jats:italic toggle=\"yes\">+\/\u0394IIA<\/jats:italic>\n                    ;\n                    <jats:italic toggle=\"yes\">Smad4+\/\u2212<\/jats:italic>\n                    mutants exhibit aggravated malformations. IIA enhances BMP-responsive reporter activity in cells in transactivation assays. We propose that IIA supports a positive functional role on SMAD4-dependent signaling, fine-tuning BMP\/TGF\u03b2 signaling, thereby regulating GATA4 and NKX2-5 activity during second heart field progenitor specification. These findings position IIA procollagen as a key ECM component that integrates BMP\/TGF\u03b2 signaling with cardiac transcription factors such as NKX2-5, revealing a feedback loop essential for cardiogenesis. Given its role in cardiac development, IIA emerges as a potential congenital heart disease risk factor.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2422592122","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T17:42:56Z","timestamp":1756921376000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Procollagen IIA mediates positive feedback control of the mouse cardiogenic transcriptional network"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3382-7947","authenticated-orcid":false,"given":"Alan W.","family":"Leung","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong","place":["Pokfulam, Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra Y.","family":"Wong","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong","place":["Pokfulam, Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet C.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong","place":["Pokfulam, Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8960-3937","authenticated-orcid":false,"given":"Keith K. 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F.","family":"Dung","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong","place":["Pokfulam, Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5116-4668","authenticated-orcid":false,"given":"Catherine A.","family":"Shang","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1600-5933","authenticated-orcid":false,"given":"Owen W.","family":"Prall","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Biology Division, Victor Chang Cardiac Research Institute","place":["Darlinghurst, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieu T.","family":"Nim","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Novo Nordisk Foundation Centre for Regenerative Medicine (reNEW) and Department of Paediatrics, The University of Melbourne","place":["Parkville, Australia"]},{"name":"Australian Regenerative Medicine Institute and Systems Biology Institute Australia, Monash University","place":["Clayton, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"See","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Novo Nordisk Foundation Centre for Regenerative Medicine (reNEW) and Department of Paediatrics, The University of Melbourne","place":["Parkville, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6315-4777","authenticated-orcid":false,"given":"Mirana","family":"Ramialison","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Novo Nordisk Foundation Centre for Regenerative Medicine (reNEW) and Department of Paediatrics, The University of Melbourne","place":["Parkville, Australia"]},{"name":"Australian Regenerative Medicine Institute and Systems Biology Institute Australia, Monash University","place":["Clayton, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-5778","authenticated-orcid":false,"given":"Danny","family":"Chan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong","place":["Pokfulam, Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Mohun","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9950-9792","authenticated-orcid":false,"given":"Richard P.","family":"Harvey","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Biology Division, Victor Chang Cardiac Research Institute","place":["Darlinghurst, Australia"]},{"name":"School of Clinical Medicine and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney","place":["Kensington, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6950-8388","authenticated-orcid":false,"given":"Patrick P. 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