Drosophila von Hippel-Lindau tumor suppressor gene function in epithelial tubule morphogenesis.
Drosophila von Hippel-Lindau tumor suppressor gene function in epithelial tubule morphogenesis.
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DOI：
10.1128/mcb.01578-09
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发表时间：
2010-08
影响因子：
5.3
通讯作者：
Hsu T
中科院分区：
文献类型：
--
作者：
Hsouna A;Nallamothu G;Kose N;Guinea M;Dammai V;Hsu T
人类von Hippel-Lindau(VHL)基因突变是VHL疾病的原因，VHL疾病表现为多种良性肿瘤和恶性肿瘤。VHL基因通过其针对缺氧诱导因子α亚基(HIF-α)的E3泛素连接酶功能来调节血管生成潜能和糖醇代谢。然而，VHL的许多不依赖于HIF的功能已经被确定。最近的证据也表明，规范功能不能完全解释VHL突变细胞的表型，尽管由于缺乏易于处理的遗传系统，目前仍不清楚这些非规范功能中有多少与病理生理过程有关。在这里，我们报道了果蝇黑腹果蝇VHL(DVHL)在上皮小管网络(气管)中的第一个基因组突变表型，并表明dVHL通过其内吞功能调节分支迁移和管腔形成。内吞功能调节趋化信号受体Breathless的表面水平，并促进气管成熟过程中管腔基质的清除。重要的是，小管形态发生的调节功能在哺乳动物系统中是保守的，因为条件基因敲除小鼠肾脏中的VHL也导致了相似的细胞运动和管腔表型。
Mutations in the human von Hippel-Lindau (VHL) gene are the cause of VHL disease that displays multiple benign and malignant tumors. The VHL gene has been shown to regulate angiogenic potential and glycolic metabolism via its E3 ubiquitin ligase function against the alpha subunit of hypoxia-inducible factor (HIF-α). However, many HIF-independent functions of VHL have been identified. Recent evidence also indicates that the canonical function cannot fully explain the VHL mutant cell phenotypes, although it is still unclear how many of these noncanonical functions relate to the pathophysiological processes because of a lack of tractable genetic systems. Here, we report the first genomic mutant phenotype of Drosophila melanogaster VHL (dVHL) in the epithelial tubule network, the trachea, and show that dVHL regulates branch migration and lumen formation via its endocytic function. The endocytic function regulates the surface level of the chemotactic signaling receptor Breathless and promotes clearing of the lumen matrix during maturation of the tracheal tubes. Importantly, the regulatory function in tubular morphogenesis is conserved in the mammalian system, as conditional knockout of Vhl in mouse kidney also resulted in similar cell motility and lumen phenotypes.