title: Arap3 is dysregulated in a mouse model of hypotrichosis-lymphedema-telangiectasia and regulates lymphatic vascular development.
abstract: Mutations in SOX18, VEGFC and Vascular Endothelial Growth Factor 3 underlie the hereditary lymphatic disorders hypotrichosis-lymphedema-telangiectasia (HLT), Milroy-like lymphedema and Milroy disease, respectively. Genes responsible for hereditary lymphedema are key regulators of lymphatic vascular development in the embryo. To identify novel modulators of lymphangiogenesis, we used a mouse model of HLT (Ragged Opossum) and performed gene expression profiling of aberrant dermal lymphatic vessels. Expression studies and functional analysis in zebrafish and mice revealed one candidate, ArfGAP with RhoGAP domain, Ankyrin repeat and PH domain 3 (ARAP3), which is down-regulated in HLT mouse lymphatic vessels and necessary for lymphatic vascular development in mice and zebrafish. We position this known regulator of cell behaviour during migration as a mediator of the cellular response to Vegfc signalling in lymphatic endothelial cells in vitro and in vivo. Our data refine common mechanisms that are likely to contribute during both development and the pathogenesis of lymphatic vascular disorders.
authors.affiliation: Division of Molecular Genetics and Development, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Kartopawiro
authors.forename: Neil I
authors.initials: NI
authors.lastname: Bower
authors.forename: Tara
authors.initials: T
authors.lastname: Karnezis
authors.forename: Jan
authors.initials: J
authors.lastname: Kazenwadel
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Betterman
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lesieur
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Koltowska
authors.forename: Jonathan
authors.initials: J
authors.lastname: Astin
authors.forename: Philip
authors.initials: P
authors.lastname: Crosier
authors.forename: Sonja
authors.initials: S
authors.lastname: Vermeren
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Smith
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Harvey
authors.forename: Mathias
authors.initials: M
authors.lastname: François
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Hogan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D007039:Hypotrichosis / Q000235:genetics*; D042583:Lymphangiogenesis / Q000235:genetics*; D042601:Lymphatic Vessels / Q000378:metabolism; D008209:Lymphedema / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D013684:Telangiectasis / Q000235:genetics*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
chemical_list: C000592378:ARAP3 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D055760:SOXF Transcription Factors; C490653:Sox18 protein, mouse; D042582:Vascular Endothelial Growth Factor C