Leung, Alan W. and Wong, Sandra Y. and Zhang, Janet C. and Leung, Keith K. H. and Dung, Nelson W. F. and Shang, Catherine A. and Prall, Owen W. and Nim, Hieu T. and See, Michael and Ramialison, Mirana and Chan, Danny and Mohun, Timothy J. and Harvey, Richard P. and Tam, Patrick P. L. and Cheah, Kathryn S. E. (2025) Procollagen IIA mediates positive feedback control of the mouse cardiogenic transcriptional network. Proceedings of the National Academy of Sciences, 122 (36). ISSN 0027-8424
Full text not available from this repository.Abstract
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 (TGFβ) 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 (ΔIIA) in mice results in depletion of Isl1- and Nkx2-5-expressing progenitors, causing outflow tract defects resembling disrupted BMP/TGFβ-SMAD signaling, alongside reduced nuclear pSMAD1/5/8 in cardiac tissues. Compound +/ΔIIA ; 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/TGFβ 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/TGFβ 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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 05 Nov 2025 04:37 |
| Last Modified: | 05 Nov 2025 04:37 |
| URI: | http://eprints.victorchang.edu.au/id/eprint/1746 |
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