title: Determination of endothelial stalk versus tip cell potential during angiogenesis by H2.0-like homeobox-1.
abstract: Tissue branching morphogenesis requires the hierarchical organization of sprouting cells into leading "tip" and trailing "stalk" cells [1, 2]. During new blood vessel branching (angiogenesis), endothelial tip cells (TCs) lead sprouting vessels, extend filopodia, and migrate in response to gradients of the secreted ligand, vascular endothelial growth factor (Vegf) [3]. In contrast, adjacent stalk cells (SCs) trail TCs, generate the trunk of new vessels, and critically maintain connectivity with parental vessels. Here, we establish that h2.0-like homeobox-1 (Hlx1) determines SC potential, which is critical for angiogenesis during zebrafish development. By combining a novel pharmacological strategy for the manipulation of angiogenic cell behavior in vivo with transcriptomic analyses of sprouting cells, we identify the uniquely sprouting-associated gene, hlx1. Expression of hlx1 is almost entirely restricted to sprouting endothelial cells and is excluded from adjacent nonangiogenic cells. Furthermore, Hlx1 knockdown reveals its essential role in angiogenesis. Importantly, mosaic analyses uncover a cell-autonomous role for Hlx1 in the maintenance of SC identity in sprouting vessels. Hence, Hlx1-mediated maintenance of SC potential regulates angiogenesis, a finding that may have novel implications for sprouting morphogenesis of other tissues.
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA. shane.herbert@manchester.ac.uk
authors.forename: Shane P
authors.initials: SP
authors.lastname: Herbert
authors.forename: Julia Y M
authors.initials: JY
authors.lastname: Cheung
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001808:Blood Vessels / Q000166:cytology* / Q000196:embryology*; D004625:Embryo, Nonmammalian; D042783:Endothelial Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; C490000:dbx1a protein, zebrafish; C051615:transgelin; D040321:Vascular Endothelial Growth Factor Receptor-3