Distinct and collaborative roles of Drosophila EXT family proteins in morphogen signalling and gradient formation
Distinct and collaborative roles of Drosophila EXT family proteins in morphogen signalling and gradient formation
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DOI：
10.1242/dev.01051
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发表时间：
2004-04-01
期刊：
影响因子：
4.6
通讯作者：
Lin, XH
中科院分区：
文献类型：
--
作者：
Han, C;Belenkaya, TY;Lin, XH
硫酸乙酰肝素蛋白聚糖; HSPG（HSPG）已经涉及调节分泌的形态发生分子的信号传导活性，包括无翅（Wg）、刺猬（Hedgehog）和十肢麻痹（Dpp）。HSPG由硫酸乙酰肝素（HS）糖胺聚糖（GAG）链连接的蛋白质核心组成。HS GAG链的形成由与遗传性多发性外生骨疣相关的推定肿瘤抑制因子EXT家族成员编码的糖基转移酶催化。先前在果蝇中的研究表明，tout-velu（ttv），果蝇EXT 1，是Hh运动所必需的。然而，其他EXT家族成员的功能尚不清楚。我们已经鉴定并分离了果蝇EXT家族的另外两个成员，它们分别被命名为tout-velu的姐妹（sotv）和tout-velu的兄弟（botv），并分别编码脊椎动物EXT 2和EXT样3（EXTL 3）的果蝇同源物。我们发现，无论是Hh和Dpp信号活动，以及它们的形态分布，是有缺陷的细胞突变体的ttv，sotv或botv在翼盘。令人惊讶的是，虽然Wg形态发生分布是异常的ttv，sotv和botv，Wg信号仅在botv突变体或ttv-sotv双突变体，而不是在ttv或sotv单独的缺陷，这表明Ttv和Sotv是多余的Wg信号。我们进一步证明，Ttv和Sotv形成一个复杂的，并在体内共定位。我们的研究结果，沿着与以前的研究Ttv，提供的证据表明，所有三个果蝇EXT蛋白所需的HSPGs的生物合成，以及梯度形成的Wg，Hh和Dpp形态发生蛋白。我们的研究结果还表明，HSPGs有两个不同的作用，Wg形态分布和信号。
Heparan sulfate proteoglycans; (HSPG) have been implicated in regulating the signalling activities of secreted morphogen molecules including Wingless (Wg), Hedgehog (Hh) and Decapentaplegic (Dpp). HSPG consists of a protein core to which heparan sulfate (HS) glycosaminoglycan (GAG) chains are attached. The formation of HS GAG chains is catalyzed by glycosyltransferases encoded by members of the EXT family of putative tumor suppressors linked to hereditary multiple exostoses. Previous studies in Drosophila demonstrated that tout-velu (ttv), the Drosophila EXT1, is required for Hh movement. However, the functions of other EXT family members are unknown. We have identified and isolated the other two members of the Drosophila EXT family genes, which are named sister of tout-velu (sotv) and brother of tout-velu (botv), and encode Drosophila homologues of vertebrate EXT2 and EXT-like 3 (EXTL3), respectively. We show that both Hh and Dpp signalling activities, as well as their morphogen distributions, are defective in cells mutant for ttv, sotv or botv in the wing disc. Surprisingly, although Wg morphogen distribution is abnormal in ttv, sotv and botv, Wg signalling is only defective in botv mutants or ttv-sotv double mutants, and not in ttv nor sotv alone, suggesting that Ttv and Sotv are redundant in Wg signalling. We demonstrate further that Ttv and Sotv form a complex and are co-localized in vivo. Our results, along with previous studies on Ttv, provide evidence that all three Drosophila EXT proteins are required for the biosynthesis of HSPGs, and for the gradient formation of the Wg, Hh and Dpp morphogens. Our results also suggest that HSPGs have two distinct roles in Wg morphogen distribution and signalling.