Multiple cardiovascular defects caused by the absence of alternatively spliced segments of fibronectin.
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.
Astrof
Sophie
S
Howard Hughes Medical Institute, Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Crowley
Denise
D
Hynes
Richard O
RO
D017398:Alternative Splicing; D000818:Animals; D018376:Cardiovascular Abnormalities / Q000235:genetics*; D002319:Cardiovascular System / Q000196:embryology*; D004622:Embryo, Mammalian / Q000378:metabolism*; D005091:Exons; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism*; D005804:Genes, Lethal; D051379:Mice; D008810:Mice, Inbred C57BL
D005353:Fibronectins
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