title: miR-221 is required for endothelial tip cell behaviors during vascular development.
abstract: Angiogenesis requires coordination of distinct cell behaviors between tip and stalk cells. Although this process is governed by regulatory interactions between the vascular endothelial growth factor (Vegf) and Notch signaling pathways, little is known about the potential role of microRNAs. Through deep sequencing and functional screening in zebrafish, we find that miR-221 is essential for angiogenesis. miR-221 knockdown phenocopied defects associated with loss of the tip cell-expressed Flt4 receptor. Furthermore, miR-221 was required for tip cell proliferation and migration, as well as tip cell potential in mosaic blood vessels. miR-221 knockdown also prevented "hyper-angiogenesis" defects associated with Notch deficiency and miR-221 expression was inhibited by Notch signaling. Finally, miR-221 promoted tip cell behavior through repression of two targets: cyclin dependent kinase inhibitor 1b (cdkn1b) and phosphoinositide-3-kinase regulatory subunit 1 (pik3r1). These results identify miR-221 as an important regulatory node through which tip cell migration and proliferation are controlled during angiogenesis.
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Nicoli
authors.forename: Carl-Philipp
authors.initials: CP
authors.lastname: Knyphausen
authors.forename: Lihua J
authors.initials: LJ
authors.lastname: Zhu
authors.forename: Abirami
authors.initials: A
authors.lastname: Lakshmanan
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Lawson
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D035683:MicroRNAs / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D051880:Receptors, Notch; D042582:Vascular Endothelial Growth Factor C; D029961:Zebrafish Proteins; C493178:vascular endothelial growth factor C, zebrafish; D019869:Phosphatidylinositol 3-Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3