FOXC2 in Hereditary Lymphedema and Lymphatic Development

遗传性淋巴水肿是淋巴系统的发育障碍，会导致毁容，通常 使四肢的浮肿(肿胀)失效，并伴有各种相关异常。大多数是常染色体 显性，有不同的表达和发病年龄。在这些情况下，主要的靶组织是淋巴管 系统，是血管系统中一个鲜为人知的组成部分，负责排出的液体的微循环 从组织和返回到血管系统，以及免疫系统的细胞运输。尽管它的 在先天性和获得性疾病中的重要性，包括癌症，对分子事件知之甚少 参与淋巴系统的发展。与许多其他发育途径一样，基因参与了 遗传性淋巴水肿可以为淋巴管生成所涉及的分子事件提供重要的见解。 我们最近发现了遗传性淋巴水肿-二叉神经症(LD)的致病基因。这种紊乱是 以淋巴水肿和眉毛腺长出的多排睫毛为特征。关联的 畸形包括法洛四联症、腭裂、胎儿积水和囊性水瘤。负责的基因 LD是FOXC2叉头家族转录因子。该项目的总体目标是确定 FOXC2与遗传性淋巴水肿和哺乳动物淋巴系统的发育有关。初步数据 提示FOXC2+/-小鼠具有高度异常的淋巴管和淋巴结，类似于 病人有身份证。具体目标是：(1)充分表征FOXC2+/-和-/-小鼠和转基因小鼠 过表达基因，用于淋巴异常作为淋巴水肿病和异常的模型系统 哺乳动物淋巴发育；(2)确定FOXC2在淋巴系统中的表达模式 在发育过程中开始评估FOXC2不足对淋巴表型和 开发；(3)开始确定FOXC2在基因控制的途径和层次中的作用 哺乳动物的淋巴管生成；(4)评估淋巴和其他异常的Foxc2缺乏的时间 通过创造在发育过程中有条件表达FOXC2的小鼠。从这些研究中，我们将学到 FOXC2缺乏导致的发育中的小鼠淋巴系统的确切缺陷 淋巴管或其他细胞类型的表达与这些缺陷相关，FOXC2不足的时间 表型，并将开始确定FOXC2在参与的复杂生化途径中的作用 淋巴管生成。

The hereditary lymphedemas are developmental disorders of the lymphatic system that lead to disfiguring and often disabling edema (swelling) of the extremities together with various associated abnormalities. Most are autosomal dominant with variable expression and age of onset. The primary target tissue in these conditions is the lymphatic system, a poorly understood component of the vascular system responsible for microcirculation of fluids drained from tissues and the return to the blood vascular system, and for trafficking cells of the immune system. Despite its importance in congenital and acquired disease, including cancer, very little is known about the molecular events involved in development of the lymphatic system. As with many other developmental pathways, genes involved in hereditary lymphedema can provide important insights into the molecular events involved in lymphangiogenesis. We recently identified the gene responsible for hereditary lymphedema-distichiasis (LD). This disorder is characterized by lymphedema and extra rows of eyelashes arising from the Meibomian glands. Associated abnormalities include tetralogy of Fallot, cleft palate, hydrops fetalis and cystic hygroma. The gene responsible for LD is the FOXC2 forkhead family transcription factor. The overall goals of this project are to determine the role of FOXC2 in hereditary lymphedema and in the development of the mammalian lymphatic system. Preliminary data indicates that Foxc2+/- mice have highly abnormal lymphatic vessels and lymph nodes analogous to those in patient's with LD. Specific aims are: (1) to fully characterize Foxc2 +/- and -/- mice, and transgenic mice overexpressing the gene, for lymphatic abnormalities as a model system for lymphedema-distichiasis and abnormal lymphatic development in mammals; (2) to determine the expression patterns of Foxc2 in the lymphatic system during development to begin to assess the mechanism of Foxc2 insufficiency on lymphatic phenotype and development; (3) to begin to establish the role of Foxc2 in the pathways and hierarchy of genes controlling lymphangiogenesis in mammals; (4) to assess the timing ofFoxc2 deficiency in lymphatic and other abnormalities by creating mice in which Foxc2 is conditionally expressed during development. From these studies we will learn the precise defects in the developing mouse lymphatic system caused by Foxc2 deficiency, whether Foxc2 expression in lymphatic or other cell types is correlated with these defects, the timing of Foxc2 insufficiency on phenotype, and will begin to determine the role of Foxc2 in the complex biochemical pathways involved in lymphangiogenesis.