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Cited by 136RNA Research and SplicingCell Adhesion Molecules ResearchDevelopmental Biology and Gene Regulation

Multiple cardiovascular defects caused by the absence of alternatively spliced segments of fibronectin

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Astrof, Sophie, Crowley, Denise, Hynes, Richard O.·2007·Developmental Biology
DOI 10.1016/j.ydbio.2007.07.005PMC PMC2080666
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Abstract

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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Crossref · 10.1016/j.ydbio.2007.07.005

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  • Mechanical signalling may play a role in the phenotypes observed in hyaluronan, FN1, and POSTN knockouts.

    “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]

    The Discussion reports cardiovascular defects in mice lacking the EIIIA and EIIIB segments of fibronectin, supporting the FN-related phenotype. It says the molecular mechanisms remain unresolved and does not propose mechanical signalling as a cause. This paper also studies loss of those splice segments rather than a complete FN1 knockout. (LLM, conf=0.78)

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  • Reduced expression of integrins essential for FN1 adhesion in Sox9 cKO and accumulation of stratified endocardium within Fn1 KO echo the phenotype observed in Sox9 cKO.

    “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]

    The “Heart defects in the EIIIA/EIIIB double-null embryos” section reports multilayered endothelium in the outflow tract or atrioventricular cushions, supporting the cited comparison to stratified endocardium. But these embryos lacked two alternatively spliced FN segments, not FN1 itself: the Abstract says FN synthesis and deposition were unaffected. The Sox9 cKO observations are the citing authors’ own comparison, not findings attributed to this source. No page numbers were supplied. (LLM, conf=0.87)

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Authors
Astrof, S., Crowley, D., & Hynes, R. O.
Affiliations
Howard Hughes Medical Institute (US)
Corresponding author
Hynes, Richard O.
ORCID
Venue
Developmental Biology
Publisher
Elsevier BV
Published
2007-11
Volume
311
Issue
1
Pages
11-24
ISSN
0012-1606 (ISSN-L)
DOI
10.1016/j.ydbio.2007.07.005
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
Licence
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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