Rotini，果蠅的GPP34 高基氏體蛋白，經由 HSPGs 調控細胞凋零的機制探討

Abstract

人類 GPP34 的果蠅同源物Ritini ( Rti）經本實驗室證實經由調控HSPGs 的表現進而調節 Hedgehog ( Hh ）型態決定因數的分佈。當Rti在翅碟細胞高量表達時引起成蟲組織萎死現象，這與 JNK 活化引起的異位細胞死亡是相關的。由於 TUNEL 測試的分佈顯示死亡細胞是散亂的產生，推測這是Rti所引起的異常二級效應。當以 3G10 抗體時，顯現高量表達 Rti 引起偵測有功能的HSPGs 量的銳減。此外 ，擴散性因數如 Hh 和 Wingless ( Wg )的正常分佈被混淆；同時， Hh 及 Decapetapleigic ( Dpp ）訊息強度都呈現下降趨勢。已知 HSPGs 參與發育訊息與型態決定因數分佈的成形，我們進一步提出高量 Rti 所引起的 JNK 細胞死亡現像是因為 HSPGs 的減量表現造成型態因數的平滑分佈被破壞所造成。

As previously reported, Ritini (Rti), a Drosophila homologue of human GPP34 family, has been suggested to participate in modulating the distribution of Hedgehog (Hh) morphogen through the extracellular heparan sulfated proteoglycans (HSPGs) by means of the mosaic study. Here, it is reported that, overexpression of Rti in wing imaginal disc cells leads to a tissue atrophy phenotype, which is associated with the induction of apoptosis by activating c-Jun N-terminal Kinase (JNK) pathway. Notably, these apoptotic cells detected from TUNEL method exhibit sporadic distribution in the GAL4 expression pattern. This finding strongly implies the case is a secondary effect caused by other possible Rti-induced abnormalities rather than Rti overexpression itself. Furthermore, a decrease of functional HSPGs was observed in Rti-overexpressing territories, where the distribution of diffusible HS-binding ligands, such as Hh and Wingless (Wg), are impaired. Meanwhile, we also noted that overexpression of Rti down-regulates the signaling activities of Hh and Decapetapleigic (Dpp), but not Wg. Today, a number of studies have illustrated that the biological function of HSPGs plays an important role in modulating developmental signals and shaping morphogen gradients. Besides, the abatement of continuities in proximodistal information causes JNK-dependent apoptosis during wing development. Taken together, we propose a model where Rti-induced apoptosis is indirectly resulted from the abnormalities of functional HSPGs in Rti-overexpressing cells, followed by disruption of smooth gradients of morphogens.