Procollagen IIA mediates positive feedback control of the mouse cardiogenic transcriptional network

• 成果类型: Article
• 署名作者: Leung, Alan W.; Wong, Sandra Y.; Zhang, Janet C.; Leung, Keith K. H.; Dung, Nelson W. F.; Shang, Catherine A.; Prall, Owen W.; Nim, Hieu T.; See, Michael; Ramialison, Mirana; Chan, Danny; Mohun, Timothy J.; Harvey, Richard P.; Tam, Patrick P. L.; Cheah, Kathryn S. E.
• 署名单位: University of Hong Kong; University of Hong Kong; Francis Crick Institute; Victor Chang Cardiac Research Institute; University of Melbourne; Murdoch Children's Research Institute; University of Melbourne; Monash University; Australian Regenerative Medicine Institute; Monash University; University of New South Wales Sydney; University of New South Wales Sydney; University of Sydney; Children's Medical Research Institute - Australia; University of Sydney
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14492
• DOI: 10.1073/pnas.2422592122
• 发表日期: 2025-09-09
• 关键词: rich amino-propeptide; twisted gastrulation; differential expression; cardiac morphogenesis; messenger-rnas; dna elements; heart field; collagen; gene; chordin

摘要

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 Col2a1 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 (TGFf3) in in vitro binding assays and acts as a BMP antagonist in amphibian embryo assays. We show that the Col2a1 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 (Delta IIA) in mice results in depletion of Isl1-and Nkx2-5-expressing progenitors, causing outflow tract defects resembling disrupted BMP/TGFf3-SMAD signaling, alongside reduced nuclear pSMAD1/5/8 in cardiac tissues. Compound +/Delta IIA; Smad4+/- 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/TGFf3 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/TGFf3 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.