The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
The Matricellular Protein CCN1 Is Essential for Cardiac Development
Open accessAbstract
The matricellular protein CCN1 (formerly named CYR61) regulates cell adhesion, migration, proliferation, survival, and differentiation through binding to integrin receptors and heparan sulfate proteoglycans. Here we show that Ccn1 -null mice are impaired in cardiac valvuloseptal morphogenesis, resulting in severe atrioventricular septal defects (AVSD). Remarkably, haploinsufficiency for Ccn1 also results in delayed formation of the ventricular septum in the embryo and persistent ostium primum atrial septal defects (ASD) in ≈20% of adults. Mechanistically, Ccn1 is not required for epithelial-to-mesenchymal transformation or cell proliferation and differentiation in the endocardial cushion tissue. However, Ccn1 deficiency leads to precocious apoptosis in the atrial junction of the cushion tissue and impaired gelatinase activities in the muscular component of the interventricular septum at embryonic day 12.5, when fusion between the endocardial cushion tissue and the atrial and ventricular septa occurs, indicating that these defects may underlie the observed AVSD. Moreover, human CCN1 maps to 1p21-p31, the chromosomal location of an AVSD susceptibility gene. Together, these results provide evidence that deficiency in matrix signaling can lead to autosomal dominant AVSD, identify Ccn1 +/− mice as a genetic model for ostium primum ASD, and implicate CCN1 as a candidate gene for AVSD in humans.
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In the citing paper
“plays essential roles in cardiovascular development during embryogenesis”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [86]
In the citing paper
“Consistent with an important role for CCN1 in angiogenesis in vivo, Ccn1-null mice are defective in placental vessel bifurcation and suffer severe cardiovascular defects [85,86].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [86]
In the citing paper
“Approximately 30% of Ccn1-null embryos fail to form chorioallantoic fusion at E8.5 and die by E9.5, whereas the remaining embryos perish at mid-gestation from placental vascular insufficiency, loss of embryonic vascular integrity, hemorrhage, and severe cardiac atrioventricular septal defect (AVSD) [85,86].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [86]
In the citing paper
“Ccn1 expression during mouse embryogenesis is tightly associated with development of the skeletal, cardiovascular, and neuronal systems [82], and targeted disruption of Ccn1 in mice results in embryonic lethality.”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [86]
In the citing paper
“Ccn1-null embryos also exhibit severe defects in atrioventricular valvuloseptal morphogenesis, resulting in a common atrioventricular valve orifice that is the hallmark of complete AVSD [86].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [86]
In the citing paper
“The mesenchymal cells in the endocardial cushion tissue suffer premature apoptosis, preventing them from fusing properly with the atrial and ventricular septa to undergo apposite valvuloseptal morphogenesis.”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [86]
In the citing paper
“Although Ccn1+/− mice are largely viable, they exhibit persistent ostium primum atrial septal defects with 20% penetrance [86].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [86]
Citations
Cites
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Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β
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Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1.
Bornstein, P. (1995) · The Journal of cell biology · doi:10.1083/jcb.130.3.503 · Cited by 666
Molecular Regulation of Atrioventricular Valvuloseptal Morphogenesis
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A genetic blueprint for cardiac development
Srivastava, D., & Olson, E. N. (2000) · Nature · doi:10.1038/35025190 · Cited by 644
Essential Role of p38α MAP Kinase in Placental but Not Embryonic Cardiovascular Development
Adams, R. H., Porrás, A., Alonso, G., Jones, M., Vintersten, K., Panelli, S., Valladares, A., Pérez, L., Klein, R., & Nebreda, Á. R. (2000) · Molecular Cell · doi:10.1016/s1097-2765(05)00014-6 · Cited by 516
Cited by
Sorted by citations
Jun, J.-I., & Lau, L. F. (2010) · Nature Cell Biology · doi:10.1038/ncb2070 · Cited by 998
“CCN1 is a potent inducer of angiogenesis and Ccn1 -null mice are embryonic lethal, owing to defects in cardiovascular developmen”
BackgroundSelf-citationTaking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets
Jun, J.-I., & Lau, L. F. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3599 · Cited by 568
Self-citationFunctions and mechanisms of action of CCN matricellular proteins
Chen, C.-C., & Lau, L. F. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2008.07.025 · Cited by 549
“These findings suggest that CCN1 may be a candidate gene for human AVSD.”
BackgroundInfluentialSelf-citationMatricellular Proteins in Cardiac Adaptation and Disease
Frangogiannis, N. G. (2012) · Physiological Reviews · doi:10.1152/physrev.00008.2011 · Cited by 459
“Although heterozygous CCN1 / mice were viable and fertile, 20% of them had ostium primum ASDs (294).”
BackgroundInfluentialCCN1/CYR61: the very model of a modern matricellular protein
Lau, L. F. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0778-3 · Cited by 338
“Consistent with an important role for CCN1 in angiogenesis in vivo, Ccn1-null mice are defective in placental vessel bifurcation and suffer severe cardiovascular defects [85, 86].”
BackgroundInfluentialSelf-citation
Metadata
- Authors
- Mo, F.-E., & Lau, L. F.
- Affiliations
- University of Illinois Chicago (US)
- Venue
- Circulation Research
- Published
- 2006-10-27
- Volume
- 99
- Issue
- 9
- Pages
- 961-969
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC1626492
- OpenAlex
- W2129300074
- Cited by
- 112
- References
- 46
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 9 · 2018: 5 · 2017: 2 · 2016: 6 · 2015: 12 · 2014: 7 · 2013: 6 · 2012: 6
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA046565, CA-46565)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- CYR61, matricellular proteins, atrioventricular septal defect, primum atrial septal defect, endocardial cushion, interventricular septum, apoptosis, gelatinase activity, haploinsufficiency, congenital heart disease, integrins, heparan sulfate proteoglycans
- MeSH terms
- Animals, Endocardium, Heart, Heart Septal Defects, Heart Septal Defects, Atrial, Heart Septum, Heart Valves, Heterozygote, Mesoderm, Mice, Transgenic, Myocardium, Apoptosis, Immediate-Early Proteins, Genetic Predisposition to Disease, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Cell Proliferation, Mice, Cysteine-Rich Protein 61
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