title: The formin FMNL3 is a cytoskeletal regulator of angiogenesis.
abstract: The process of angiogenesis requires endothelial cells (ECs) to undergo profound changes in shape and polarity. Although this must involve remodelling of the EC cytoskeleton, little is known about this process or the proteins that control it. We used a co-culture assay of angiogenesis to examine the cytoskeleton of ECs actively undergoing angiogenic morphogenesis. We found that elongation of ECs during angiogenesis is accompanied by stabilisation of microtubules and their alignment into parallel arrays directed at the growing tip. In other systems, similar microtubule alignments are mediated by the formin family of cytoskeletal regulators. We screened a library of human formins and indentified formin-like 3 (FMNL3; also known as FRL2) as a crucial regulator of EC elongation during angiogenesis. We showed that activated FMNL3 triggers microtubule alignment and that FMNL3 is required for this alignment during angiogenic morphogenesis. FMNL3 was highly expressed in the ECs of zebrafish during development and embryos that were depleted for FMNL3 showed profound defects in developmental angiogenesis that were rescued by expression of the human gene. We conclude that FMNL3 is a new regulator of endothelial microtubules during angiogenesis and is required for the conversion of quiescent ECs into their elongated angiogenic forms.
authors.affiliation: School of Biochemistry, Medical Sciences Building, University Walk, University of Bristol, Bristol, BS8 1TD,  UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Hetheridge
authors.forename: Alice N
authors.initials: AN
authors.lastname: Scott
authors.forename: Rajeeb K
authors.initials: RK
authors.lastname: Swain
authors.forename: John W
authors.initials: JW
authors.lastname: Copeland
authors.forename: Henry N
authors.initials: HN
authors.lastname: Higgs
authors.forename: Roy
authors.initials: R
authors.lastname: Bicknell
authors.forename: Harry
authors.initials: H
authors.lastname: Mellor
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D003599:Cytoskeleton / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D000080865:Formins; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011506:Proteins / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C476209:FMNL3 protein, human; C578075:FMNL3 protein, zebrafish; D000080865:Formins; D008565:Membrane Proteins; D011506:Proteins; D029961:Zebrafish Proteins