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First published online 5 November 2008
doi: 10.1242/dev.029736

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Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126

Frank Kuhnert^1,*, Michael R. Mancuso^1,*, Jessica Hampton¹, Kryn Stankunas², Tomoichiro Asano³, Chang-Zheng Chen⁴ and Calvin J. Kuo^1,

¹ Division of Hematology, Department of Medicine, Stanford University School of Medicine, CCSR 1155, 269 Campus Drive, Stanford, CA 94305, USA.
² Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CCSR 1155, 269 Campus Drive, Stanford, CA 94305, USA.
³ Department of Medical Science, Graduate School of Medicine, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
⁴ Baxter Laboratory and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Author for correspondence (e-mail: cjkuo{at}stanford.edu)

Accepted 7 October 2008

SUMMARY

Intronic microRNAs have been proposed to complicate the design and interpretation of mouse knockout studies. The endothelial-expressed Egfl7/miR-126 locus contains miR-126 within Egfl7 intron 7, and angiogenesis deficits have been previously ascribed to Egfl7 gene-trap and lacZ knock-in mice. Surprisingly, selectively floxed Egfl7 and miR-126 alleles revealed that Egfl7^/ mice were phenotypically normal, whereas miR-126^/ mice bearing a 289-nt microdeletion recapitulated previously described Egfl7 embryonic and postnatal retinal vascular phenotypes. Regulation of angiogenesis by miR-126 was confirmed by endothelial-specific deletion and in the adult cornea micropocket assay. Furthermore, miR-126 deletion inhibited VEGF-dependent Akt and Erk signaling by derepression of the p85β subunit of PI3 kinase and of Spred1, respectively. These studies demonstrate the regulation of angiogenesis by an endothelial miRNA, attribute previously described Egfl7 vascular phenotypes to miR-126, and document inadvertent miRNA dysregulation as a complication of mouse knockout strategies.

Key words: Angiogenesis, miRNA, miR-126 (Mirn126), Egfl7, p85β (Pik3r2)

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