Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is required for branching morphogenesis in the chorioallantoic placenta
Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is required for branching morphogenesis in the chorioallantoic placenta
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DOI：
10.1128/mcb.25.13.5687-5698.2005
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
Kataoka, H
中科院分区：
文献类型：
--
作者：
Tanaka, H;Nagaike, K;Kataoka, H
肝细胞生长因子激活物抑制剂1型（HAI-1）是一种膜相关的Kunitz型丝氨酸蛋白酶抑制剂，最初被鉴定为肝细胞生长因子激活物的有效抑制剂。HAI-1也是间质蛋白酶（一种膜相关丝氨酸蛋白酶）的同源抑制剂。HAI-1主要在人体的上皮细胞中表达。其mRNA在人胎盘中也很丰富，HAI-1由绒毛细胞滋养层细胞特异性表达。为了阐明HAI-1在体内的确切作用，我们通过纯合重组产生HAI-1突变小鼠。杂合HAI-1（+/-）小鼠经历正常器官发育。然而，纯合子HAI-1（-/-）小鼠经历了胚胎致死性，这在胚胎发育后10.5天（E10.5）变得明显。早在E9.5，HAI-1（-/-）胚胎表现出生长迟缓，这并不反映受损的细胞增殖，而是由于胎盘发育和功能失败。组织学分析显示迷路层的形成严重受损，相反，所有其他胎盘层，如海绵滋养层和巨细胞层，形成。我们的研究结果表明，小鼠HAI-1是必不可少的分支形态发生在绒毛尿囊胎盘和缺乏HAI-1功能可能会导致胎盘衰竭。
Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-associated Kunitz-type serine proteinase inhibitor that was initially identified as a potent inhibitor of hepatocyte growth factor activator. HAI-1 is also a cognate inhibitor of matriptase, a membrane-associated serine proteinase. HAI-1 is expressed predominantly in epithelial cells in the human body. Its mRNA is also abundant in human placenta, with HAI-1 specifically expressed by villous cytotrophoblasts. In order to address the precise roles of HAI-1 in vivo, we generated HAI-1 mutant mice by homozygous recombination. Heterozygous HAI-1(+/-) mice underwent normal organ development. However, homozygous HAI-1(-/-) mice experienced embryonic lethality which became evident at embryonic day 10.5 postcoitum (E10.5). As early as E9.5, HAI-1(-/-) embryos showed growth retardation that did not reflect impaired cell proliferation but resulted instead from failed placental development and function. Histological analysis revealed severely impaired formation of the labyrinth layer, in contrast all other placental layers, such as the spongiotrophoblast layer and giant cell layer, which were formed. Our results indicate that mouse HAI-1 is essential for branching morphogenesis in the chorioallantoic placenta and lack of HAI-1 function may result in placental failure.