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: Joëlle Kartopawiro, Neil I Bower, Tara Karnezis, Jan Kazenwadel, Kelly L Betterman, Emmanuelle Lesieur, Katarzyna Koltowska, Jonathan Astin, Philip Crosier, Sonja Vermeren, Marc G Achen, Steven A Stacker, Kelly A Smith, Natasha L Harvey, Mathias François, Benjamin M Hogan
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 5 Pg. 1286-97 (Mar 01 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24163130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARAP3 protein, mouse
• Adaptor Proteins, Signal Transducing
• GTPase-Activating Proteins
• SOXF Transcription Factors
• Sox18 protein, mouse
• Vascular Endothelial Growth Factor C

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Cell Movement (genetics)
• Disease Models, Animal
• Endothelial Cells (metabolism)
• Female
• GTPase-Activating Proteins (genetics, metabolism)
• Gene Expression Regulation
• Hypotrichosis (genetics)
• Lymphangiogenesis (genetics)
• Lymphatic Vessels (metabolism)
• Lymphedema (genetics)
• Mice
• Mice, Knockout
• SOXF Transcription Factors (genetics, metabolism)
• Syndrome
• Telangiectasis (genetics)
• Vascular Endothelial Growth Factor C (genetics, metabolism)
• Zebrafish