Redundant roles of Sox17 and Sox18 in postnatal angiogenesis in mice
Redundant roles of Sox17 and Sox18 in postnatal angiogenesis in mice
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DOI：
10.1242/jcs.03081
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发表时间：
2006-09-01
影响因子：
4
通讯作者：
Kanai, Yoshiakira
中科院分区：
文献类型：
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作者：
Matsui, Toshiyasu;Kanai-Azuma, Masami;Kanai, Yoshiakira
Sox7、Sox17和Sox18构成HMG盒转录因子基因Sox家族的F族。在衣衫褴褛的突变小鼠中观察到的Sox18的显性负突变是心血管缺陷的基础。相比之下，Sox18（-/-）小鼠是可存活和可生育的，它们的脉管系统没有明显的异常，表明其他两个SoxF基因的功能补偿。在这里，我们通过产生Sox17(+/-)-Sox18（-/-）双突变小鼠，为Sox17和Sox18在出生后新生血管中的冗余功能提供了直接证据。而Sox18（-/-）和Sox17(+/-)-Sox18(+/ -)-小鼠没有血管缺陷，大约一半的Sox17(+/-)-Sox18（-/-）幼崽在出生后21天前死亡（P21）。肝窦和肾外髓直血管在P7时新生血管减少，这很可能导致肝细胞和肾小管上皮在P14中观察到的缺血性坏死。那些存活到成年的雄鼠在肝脏和肾脏都表现出类似但较轻微的血管异常，雌鼠在生殖器官中表现出不同程度的血管异常，无法生育。这些异常与出生后发育中的血管中Sox7和Sox17的表达位点一致。体外血管生成实验，使用从P7肝脏分离的原代内皮细胞，显示Sox17(+/-)- sox18（-/-）内皮细胞在内皮发芽和血管重塑中以表型依赖的方式存在缺陷。因此，我们的研究结果表明，Sox17和Sox18，可能是所有三个SoxF基因，共同参与哺乳动物血管发育。
Sox7, Sox17 and Sox18 constitute group F of the Sox family of HMG box transcription factor genes. Dominant-negative mutations in Sox18 underlie the cardiovascular defects observed in ragged mutant mice. By contrast, Sox18(-/-) mice are viable and fertile, and display no appreciable anomaly in their vasculature, suggesting functional compensation by the two other SoxF genes. Here, we provide direct evidence for redundant function of Sox17 and Sox18 in postnatal neovascularization by generating Sox17(+/-)-Sox18(-/-) double mutant mice. Whereas Sox18(-/-) and Sox17(+/-)-Sox18(+/)-mice showed no vascular defects, approximately half of the Sox17(+/-)-Sox18(-/-) pups died before postnatal day 21 (P21). They showed reduced neovascularization in the liver sinusoids and kidney outer medulla vasa recta at P7, which most likely caused the ischemic necrosis observed by P14 in hepatocytes and renal tubular epithelia. Those that survived to adulthood showed similar, but milder, vascular anomalies in both liver and kidney, and females were infertile with varying degrees of vascular abnormalities in the reproductive organs. These anomalies corresponded with sites of expression of Sox7 and Sox17 in the developing postnatal vasculature. In vitro angiogenesis assays, using primary endothelial cells isolated from the P7 livers, showed that the Sox17(+/-)-Sox18(-/-)endothelial cells were defective in endothelial sprouting and remodeling of the vasculature in a phenotype-dependent manner. Therefore, our findings indicate that Sox17 and Sox18, and possibly all three SoxF genes, are cooperatively involved in mammalian vascular development.