Arap3 is dysregulated in a mouse model of hypotrichosis-lymphedema-telangiectasia and regulates lymphatic vascular development
Arap3 is dysregulated in a mouse model of hypotrichosis-lymphedema-telangiectasia and regulates lymphatic vascular development
复制标题
DOI：
10.1093/hmg/ddt518
复制
发表时间：
2014-03-01
影响因子：
3.5
通讯作者：
Hogan, Benjamin M.
中科院分区：
文献类型：
--
作者：
Kartopawiro, Joelle;Bower, Neil I.;Hogan, Benjamin M.
S 0X 18、VEGFC和血管内皮生长因子3中的突变分别是遗传性淋巴系统疾病低渗性水肿-毛细血管扩张（HLT）、Milroy样水肿和Milroy病的基础。遗传性水肿的基因是胚胎中淋巴管发育的关键调节因子。为了鉴定淋巴管生成的新调节剂，我们使用了HLT（粗糙负鼠）小鼠模型，并对异常真皮淋巴管进行了基因表达谱分析。在斑马鱼和小鼠中的表达研究和功能分析揭示了一个候选者，具有RhoGAP结构域、锚蛋白重复序列和PH结构域3（ARAP 3）的ArfGAP，其在HLT小鼠淋巴管中下调，并且是小鼠和斑马鱼中淋巴管发育所必需的。我们将这种已知的细胞行为调节剂在迁移过程中作为细胞反应的介体Vegfc信号在淋巴管内皮细胞在体外和体内。我们的数据细化共同的机制，可能有助于在发展和淋巴血管疾病的发病机制。
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.