- 學位論文
高基氏體蛋白與多醣蛋白HSPGs協同影響形態決定素分布模式之探討
The appoach of Golgi proteins and heparan sulfate proteoglycans (HSPGs) in the regulation of morphogen distribution in Drosophila
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摘要
形態決定素(morphogen)是具有訊息傳遞能力的蛋白質，在發育組織中各有其獨特的濃度梯度。藉此，接受不等訊息強度的細胞群會開啟特定的下游基因表現，進而引導了細胞命運的正確決定與發育過程的進行。近年來的研究顯示，位於細胞膜上的巨型多醣蛋白HSPGs對於形態決定素Hedgehog(Hh), Wingless(Wg), Decapentaplegics(Dpp)在果蠅翅碟上的移動與訊息傳遞皆扮演重要的角色。我們先前的研究指出一個新發現的節向決定基因Rotini(Rti)能決定HSPGs的表現，同時也影響到形態決定素的行為。我們更發現Rti座落於高基氏體，且能夠直接與一個可能的v-SNARE, dVti1交互作用。這些資訊顯示Rti應是一個參與於蛋白質運輸的新成員，並且由Rti調控的輸送過程可能決定了HSPGs合成的正確發生，因此引發了後續對於形態決定素的廣泛影響。 此外，合成HSPGs的核心蛋白Dally-like(Dlp)，在翅碟上具有一特殊的分布: Dlp在翅碟腹背交界處表現量極低，而此處正是Wg分泌的所在。我們進一步證明了Wg的訊息傳遞對於Dlp的抑制作用不僅是必須性的，且足以在Wing pouch及notum上被異位引發。由於Dlp的表現能夠擴大Wg在翅碟上的分布，因此形態決定素Wg可以藉由其訊息傳遞路徑對Dlp產生抑制作用，以此來回饋調控本身的散佈範圍。這些結果顯示形態決定素與多醣蛋白HSPGs之間的調控關係是互為因果的。
並列摘要
Morphogens are signaling proteins which form their own specific gradients over the developing tissues and subsequently pattern the field by activating different sets of genes at distinct signaling intensities. In recent years, macromolecules heparan sulfate proteoglycans (HSPGs) which locate on the cell surface were found to be essential for modulating the movement and distribution of multiple morphogens such as Hedgehog (Hh), Wingless (Wg) and Decapentaplegics (Dpp) in Drosophila wing imaginal discs. In previous studies, we identified a novel segment polarity gene, rotini (rti), which determines the distribution of these essential morphogens and is required for the normal expression of functional HSPGs. Additionally, we found Rti is a Golgi-resided protein and capable to physically interact with a putative V-SNARE, dVti1, that is a core member in the process of vesicle traffickings. Therefore, we suggest that Rti is a novel component in the trafficking pathway and the Rti-mediated transportation is necessary for the biosynthesis of functional HSPGs, which in turn influences the HSPGs-controlled morphogen behaviors on the cell surface. Moreover, we found one glypican of HSPGs core proteins, Dally-like (Dlp), is almost absent within cells along the D-V boundary of wing discs, and this pattern is roughly complementary to Wg expression. Our analysis showed that high level of Wg signaling is not only necessary but also sufficient to repress Dlp expression in the wing pouch and notum region in wing discs. As the Dlp-composed HSPGs are potent to modulate Wg distribution, we suggest that Wg can restrict its own spreading range via its own signaling. It also indicates that the regulations on HSPGs and morphogens are interdependent.
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