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Multiple cardiovascular defects caused by the absence of alternatively spliced segments of fibronectin
Open accessAbstract
Alternatively spliced variants of fibronectin (FN) containing exons EIIIA and EIIIB are expressed around newly forming vessels in development and disease but are downregulated in mature vasculature. The sequences and patterns of expression of these splice variants are highly conserved among vertebrates, suggestive of their biological importance; however the functions of EIIIA and EIIIB-containing FNs are unknown. To understand the role(s) of these splice variants, we deleted both EIIIA and EIIIB exons from the FN gene and observed embryonic lethality with incomplete penetrance by embryonic day 10.5. Deletion of both EIIIA and EIIIB exons did not affect synthesis or cell surface deposition of FN, indicating that embryonic lethality was due specifically to the absence of EIIIA and EIIIB exons from FN. EIIIA/EIIIB double-null embryos displayed multiple embryonic cardiovascular defects, including vascular hemorrhage, failure of remodeling embryonic and yolk sac vasculature, defective placental angiogenesis and heart defects. In addition, we observed defects in coverage and association with dorsal aortae of alpha-smooth-muscle-actin-positive cells. Our studies indicate that the presence or absence of EIIIA and EIIIB exons alters the function of FN and demonstrate the requirement for these alternatively spliced exons in cardiovascular development.
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“Mechanical signalling may play a role in the phenotypes observed in the hyaluronan71, FN157, and POSTN72 knockouts, for which the latter is already known to mediate atrioventricular development through integrin signalling.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [57]
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“The latter is supported by the reduced expression of integrins essential for FN1 adhesion in the Sox9 cKO, along with the accumulation of stratified endocardium within the Fn1 KO, which echoes the phenotype we observe in the Sox9 cKO57.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [57]
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Metadata
- Authors
- Astrof, S., Crowley, D., & Hynes, R. O.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Hynes, Richard O.
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 311
- Issue
- 1
- Pages
- 11-24
- ISSN
- 0012-1606 (ISSN-L)
- PMC
- PMC2080666
- OpenAlex
- W2035642405
- Semantic Scholar
- 19181f6bc6b527bcd2588ec8f258342672b22faa
- Cited by
- 136
- References
- 57
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 7 · 2022: 8 · 2021: 7 · 2020: 10 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 6
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2121 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01HL066105)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- fibronectin, alternative splicing, cardiovascular development, embryonic lethality, yolk sac vasculature, placental angiogenesis, cardiac anomalies, alpha-smooth muscle actin, dorsal aorta, gene deletion
- MeSH terms
- Animals, Cardiovascular System, Embryo, Mammalian, Exons, Extracellular Matrix, Fibroblasts, Fibronectins, Genes, Lethal, Mice, Inbred C57BL, Alternative Splicing, Cardiovascular Abnormalities, Mice
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