Reversion of lethality and growth defects in Fatiga oxygen-sensor mutant flies by loss of Hypoxia-inducible Factor-α/Sima
Reversion of lethality and growth defects in Fatiga oxygen-sensor mutant flies by loss of Hypoxia-inducible Factor-α/Sima
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DOI：
10.1038/sj.embor.7400528
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发表时间：
2005-11-01
期刊：
影响因子：
7.7
通讯作者：
Wappner, P
中科院分区：
文献类型：
--
作者：
Centanin, L;Ratcliffe, PJ;Wappner, P
缺氧诱导因子 (HIF) 脯氨酰羟化酶结构域 (PHD) 已被提议作为传感器，在氧稳态中发挥重要作用。在氧气存在的情况下，它们使 HIF-α 多肽中的两个特定脯氨酰残基羟基化，从而促进其蛋白酶体降解。然而，迄今为止，高等后生动物中 PHD 失活的发育后果尚未有报道。在这里，我们描述了 Fatiga 的新型功能丧失突变体，该基因编码果蝇 PHD 氧传感器，表现出生长缺陷和致死性。我们还报告了 dHIF-alpha/sima 的无效突变，它无法适应缺氧，但在含氧量正常的条件下完全可行。引人注目的是，sima 的功能丧失突变挽救了在 fatiga 突变体中观察到的发育缺陷，并使它们能够存活到成年。这些结果表明 Fatiga 在发育过程中的主要功能，包括控制细胞大小，涉及 dHIF/Sima 的调节。
Hypoxia-Inducible Factor (HIF) prolyl hydroxylase domains (PHDs) have been proposed to act as sensors that have an important role in oxygen homeostasis. In the presence of oxygen, they hydroxylate two specific prolyl residues in HIF-alpha polypeptides, thereby promoting their proteasomal degradation. So far, however, the developmental consequences of the inactivation of PHDs in higher metazoans have not been reported. Here, we describe novel loss-of-function mutants of fatiga, the gene encoding the Drosophila PHD oxygen sensor, which manifest growth defects and lethality. We also report a null mutation in dHIF-alpha/sima, which is unable to adapt to hypoxia but is fully viable in normoxic conditions. Strikingly, loss-of-function mutations of sima rescued the developmental defects observed in fatiga mutants and enabled survival to adulthood. These results indicate that the main functions of Fatiga in development, including control of cell size, involve the regulation of dHIF/Sima.