ArticleMatrix biology : journal of the International Society for Matrix Biology2024
Combined genetic-pharmacologic inactivation of tightly linked ADAMTS proteases in temporally specific windows uncovers distinct roles for versican proteolysis and glypican-6 in cardiac development.
Article in Matrix biology : journal of the International Society for Matrix Biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Review
- GPC6 facilitates progression of SHH-subgroup medulloblastoma by enhancing Hedgehog secretion and signaling responses.Journal of biomedical research · 2026Article
- Neural Organoids Protect Engineered Heart Tissues From Glucolipotoxicity by Transferring Versican in a Co-Culture System.Cell proliferation · 2026Article
- An Overview of ADAMTS Proteases.Methods in molecular biology (Clifton, N.J.) · 2026Review
- Temporal expression dynamics of glypicans during hiPSC cardiac differentiation.Frontiers in cell and developmental biology · 2026Article
- Adamts1 Exacerbates Post-Myocardial Infarction Scar Formation via Mechanosensing of Integrin α8.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
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10 authors.
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Abstract
Extracellular matrix remodeling mechanisms are understudied in cardiac development and congenital heart defects. We show that matrix-degrading metalloproteases ADAMTS1 and ADAMTS5, are extensively co-expressed during mouse cardiac development. The mouse mutants of each gene have mild cardiac anomalies, however, their combined genetic inactivation to elicit cooperative roles is precluded by tight gene linkage. Therefore, we coupled Adamts1 inactivation with pharmacologic ADAMTS5 blockade to uncover stage-specific cooperative roles and investigated their potential substrates in mouse cardiac development. ADAMTS5 blockade was achieved in Adamts1 null mouse embryos using an activity-blocking monoclonal antibody during distinct developmental windows spanning myocardial compaction or cardiac septation and outflow tract rotation. Synchrotron imaging, RNA in situ hybridization, immunofluorescence microscopy and electron microscopy were used to determine the impact on cardiac development and compared to Gpc6 and ADAMTS-cleavage resistant versican mutants. Mass spectrometry-based N-terminomics was used to seek relevant substrates. Combined inactivation of ADAMTS1 and ADAMTS5 prior to 12.5 days of gestation led to dramatic accumulation of versican-rich cardiac jelly and inhibited formation of compact and trabecular myocardium, which was also observed in mice with ADAMTS cleavage-resistant versican. Combined inactivation after 12.5 days impaired outflow tract development and ventricular septal closure, generating a tetralogy of Fallot-like defect. N-terminomics of combined ADAMTS knockout and control hearts identified a cleaved glypican-6 peptide only in the controls. ADAMTS1 and ADAMTS5 expression in cells was associated with specific glypican-6 cleavages. Paradoxically, combined ADAMTS1 and ADAMTS5 inactivation reduced cardiac glypican-6 and outflow tract Gpc6 transcription. Notably, Gpc6
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