Redundant roles ofSox17andSox18in postnatal angiogenesis in mice

Abstract

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.

The lymphangiogenic factor SOX 18: A key indicator to stage gastric tumor progression

“…[19][20][21][22][23][24][25][26][27][28][29][30] In fact, few studies have revealed the significance of SOX group F gene expression in human cancer, although cell line-based studies have demonstrated that both SOX 18 and SOX 7 were highly expressed in several strains of gastric, pancreatic and esophageal cancer cell lines. 22,32 In the present study, SOX group F gene expression determined by RT-PCT was increased in gastric cancer tissues than in normal gastric tissues obtained from the same individuals.…”

“…17 SOX 18 is transiently expressed in the endothelial cells of all developing blood vessels and has a key role in both vascular development and postnatal neovascularization. 15,[19][20][21] SOX 18 is highly expressed in the ventricles and interventricular septum of the normal adult heart, and relatively highly expressed in the gastrointestinal tract, i.e., in the stomach and jejunum. 22 SOX 18 expression is also reactivated during adult neovascularization associated with wound healing and tumorigenesis.…”

“…[25][26][27][28] The SOX 7 and SOX 17 genes are also known to have compensatory roles during angiogenesis and lymphangiogenesis. [19][20][21] It has been demonstrated that blood circulation in SOX 7 and SOX 18 double knock-down zebrafish was blocked in the trunk and tail due to multiple fusions between the axial vessels. 19 Furthermore, SOX 17/SOX 18-double null mouse embryos also developed severe abnormal defects during the formation of the anterior dorsal aorta and of the cervical microvasculature.…”

SOX17 antagonizes WNT/β-catenin signaling pathway in hepatocellular carcinoma

“…[28][29][30][31] Embryonic lethality is common in SOX17-null embryos due to deficiency of gut definitive endoderm. 32 In Xenopus laevis, SOX17 cooperates with β-catenin to activate the transcription of endoderm target genes.…”

Development of the kidney medulla

“…42 Double-mutant mice deficient in high mobility group (HMG) box transcription factor genes Sox17/Sox18, show reduced neovascularization in the outer medulla vasa recta on postnatal day 7. 43 Notably, AT1R or Sox17 mutations are causative factors in CAKUT in humans. 44,45 Whether structural maldevelopment of the medulla affects vasa recta formation or defects in vascular development account for decreased size of the medulla remains to be determined.…”