Alternative titles; symbols
HGNC Approved Gene Symbol: EGFL7
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38) : 9:136,658,856-136,672,678 (from NCBI)
Soncin et al. (2003) cloned 2 splice variants of mouse Egfl7, which they designated VE-statin. The variants differ in their first exons but encode identical proteins. The deduced 275-amino acid protein has a calculated molecular mass of 29.8 kD. By RT-PCR and 5-prime RACE, Soncin et al. (2003) cloned 2 splice variants of human EGFL7, both of which encode a deduced 273-amino acid protein with a calculated molecular mass of 29.6 kD. The mouse and human EGFL7 proteins both contain an N-terminal cleavable signal peptide followed by 2 epidermal growth factor (EGF; 131530)-like domains, and they share 78% amino acid identity. Northern blot analysis detected a transcript of about 1.6 kb only in mouse heart, lung, and kidney. In situ hybridization showed mouse Egfl7 expressed at embryonic day 7.5 exclusively in the primitive blood islands where the first endothelial cells differentiate, and later in endothelial cells of a wide range of tissues. Fluorescence-labeled Egfl7 was expressed in the endoplasmic reticulum of transfected mouse fibroblasts, and it was secreted into the culture medium.
Fitch et al. (2004) cloned a mouse Egfl7 cDNA encoding a deduced 278-amino acid protein with a calculated molecular mass of 29 kD. Northern blot analysis detected highest Egfl7 expression in mouse lung, with lower expression in heart, ovary, uterus, and kidney. EGFL7 expression was also detected in human umbilical vein endothelial cells. Human embryonic kidney cells transfected with cDNA for fluorescence-tagged mouse Egfl7 expressed the protein in a punctate, perinuclear distribution. Western blot analysis detected Egfl7 at an apparent molecular mass of 41 kD, suggesting posttranslational modification.
Schmidt et al. (2009) noted that EGFL7 contains an N-terminal signal sequence, followed by a cysteine-rich emilin (see 130660)-like (EMI) domain and 2 EGF-like domains. RT-PCR detected Egfl7 in mouse brain, predominantly in cortex. Immunohistochemical analysis revealed that Egfl7 was expressed predominantly in neurons.
Soncin et al. (2003) determined that the mouse Egfl7 gene contains 11 exons, including alternate first exons, and spans more than 10 kb. The 5-prime UTR contains 2 SINEs, and the ATG start codon is located in exon 3. The human EGFL7 gene is similarly organized, but it contains 3 SINEs in the 5-prime UTR.
Zhang et al. (2008) noted that the microRNA-126 gene (MIR126; 611767) is located within intron 5 of the EGFL7 gene. Wang et al. (2008) stated that MIR126 is located within intron 7 of EGFL7.
By FISH and radiation hybrid analysis, Soncin et al. (2003) mapped the EGFL7 gene to chromosome 9q34.3-qter. They mapped the mouse Egfl7 gene to chromosome 2B.
Gross (2016) mapped the EGFL7 gene to chromosome 9q34.3 based on an alignment of the EGFL7 sequence (GenBank AF186111) with the genomic sequence (GRCh38).
Soncin et al. (2003) found that recombinant Egfl7 purified from the conditioned medium of transfected mouse fibroblasts inhibited PDGF (see 190040)-induced aortic smooth muscle cell migration, but it had no effect on endothelial cell migration. Egfl7 had no effect on smooth muscle cell proliferation.
Parker et al. (2004) demonstrated that EGFL7 is expressed at high levels in the vasculature associated with tissue proliferation, and is downregulated in most of the mature vessels in normal adult tissues. Loss of Egfl7 function in zebrafish embryos specifically blocked vascular tubulogenesis. Parker et al. (2004) uncovered a dynamic process during which gradual separation and proper spatial arrangement of the angioblasts allows subsequent assembly of vascular tubes. This process failed to take place in Egfl7 knockdown embryos, leading to the failure of vascular tube formation. Parker et al. (2004) concluded that their study defined Egfl7 as a regulator that controls a specific and important step in vasculogenesis.
Using human EGFL7 as bait for yeast 2-hybrid analysis of human tissues, Schmidt et al. (2009) showed that EGFL7 interacted with the extracellular domains of NOTCH1 (190198), NOTCH2 (600275), NOTCH3 (600276), and NOTCH4 (164951). Mutation analysis revealed that binding to Notch proteins required the EMI domain of EGFL7 and that the EGF-like domains of EGFL7 strengthened the interaction. Secreted EGFL7 bound the Notch extracellular domain, competed with the Notch ligands JAG1 (601920) and JAG2 (602570) for Notch binding, and inhibited Notch signaling. Expression of mouse or human EGFL7 in mouse neural stem cells decreased Notch signaling, reducing cell proliferation and self-renewal potential. EGFL7-mediated inhibition of Notch signaling increased differentiation of neural stem cells into neurons and oligodendrocytes and reduced their differentiation into astrocytes. Schmidt et al. (2009) concluded that EGFL7 acts as an endogenous antagonist of Notch signaling and regulates proliferation and differentiation of subventricular zone-derived adult neural stem cells.
Using zebrafish mutants and morpholino-mediated knockdown of genes in zebrafish embryos, Renz et al. (2015) identified a proangiogenic signaling pathway that involved activation of beta-1 integrin (ITGB1; 135630), followed by elevated expression of klf2a (see 602016), klf2b, egfl7, and vegf (VEGFA; 192240). Ccm2 (607929) negatively regulated this pathway. Loss of ccm2 elevated expression of several genes related to angiogenesis, including klf2a and klf2b, and resulted in significant cardiovascular malformations. These defects occurred in the absence of blood flow and did not require mir126a or mir126b, the latter of which is located within the egfl7 gene. Knockdown of beta-1 integrin reversed the cardiovascular defects in ccm2 mutant embryos. Knockout of Ccm2 in mice also resulted in elevated Klf2 expression and cardiovascular defects. Renz et al. (2015) concluded that the beta-1 integrin-KLF2-EGFL7 pathway is tightly regulated by CCM2 and that this regulation prevents angiogenic overgrowth and ensures quiescence in endothelial cells.
Fitch, M. J., Campagnolo, L., Kuhnert, F., Stuhlmann, H. Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells. Dev. Dyn. 230: 316-324, 2004. [PubMed: 15162510] [Full Text: https://doi.org/10.1002/dvdy.20063]
Gross, M. B. Personal Communication. Baltimore, Md. 11/30/2016.
Parker, L. H., Schmidt, M., Jin, S.-W., Gray, A. M., Beis, D., Pham, T., Frantz, G., Palmieri, S., Hillan, K., Stainier, D. Y. R., de Sauvage, F. J., Ye, W. The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature 428: 754-758, 2004. [PubMed: 15085134] [Full Text: https://doi.org/10.1038/nature02416]
Renz, M., Otten, C., Faurobert, E., Rudolph, F., Zhu, Y., Boulday, G., Duchene, J., Mickoleit, M., Dietrich, A.-C., Ramspacher, C., Steed, E., Manet-Dupe, S., and 9 others. Regulation of beta-1 integrin-Klf2-mediated angiogenesis by CCM proteins. Dev. Cell 32: 181-190, 2015. [PubMed: 25625207] [Full Text: https://doi.org/10.1016/j.devcel.2014.12.016]
Schmidt, M. H. H., Bicker, F., Nikolic, I., Meister, J., Babuke, T., Picuric, S., Muller-Esterl, W., Plate, K. H., Dikic, I. Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nature Cell Biol. 11: 873-880, 2009. Note: Erratum: Nature Cell Biol. 11: 1043 only, 2009. [PubMed: 19503073] [Full Text: https://doi.org/10.1038/ncb1896]
Soncin, F., Mattot, V., Lionneton, F., Spruyt, N., Lepretre, F., Begue, A., Stehelin, D. VE-statin, an endothelial repressor of smooth muscle cell migration. EMBO J. 22: 5700-5711, 2003. [PubMed: 14592969] [Full Text: https://doi.org/10.1093/emboj/cdg549]
Wang, S., Aurora, A. B., Johnson, B. A., Qi, X., McAnally, J., Hill, J. A., Richardson, J. A., Bassel-Duby, R., Olson, E. N. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev. Cell 15: 261-271, 2008. [PubMed: 18694565] [Full Text: https://doi.org/10.1016/j.devcel.2008.07.002]
Zhang, J., Du, Y., Lin, Y., Chen, Y., Yang, L., Wang, H., Ma, D. The cell growth suppressor, mir-126, targets IRS-1. Biochem. Biophys. Res. Commun. 377: 136-140, 2008. [PubMed: 18834857] [Full Text: https://doi.org/10.1016/j.bbrc.2008.09.089]