2014-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658846摘要：細胞遷移在動物發育扮演非常重要的角色，也是細胞生物學與發育生物學研究的重點。正常的細胞遷移需要整合時間和空間上的訊息，儘管許多空間上的調控分子已經被詳細研究，但是對於時間的調控以及如何整合時間與空間的調控訊息仍所知甚少。線蟲(C. elegans)中的遠端細胞(Distal tip cells, DTCs)是研究細胞遷移很好的模型，遠端細胞在第一幼蟲期會在腹側中央產生，並且會在第三幼蟲期往背側遷移而引導生殖腺的延伸方向。F-box蛋白質DRE-1、鋅指轉錄調控子LIN-29和DAF-12協同作用而控制DTC細胞背向遷移的時間點，這表示遠端細胞遷移的時間控制仰賴基因表現和蛋白質降解的調控，我們先前發現鋅指轉錄調控子DPY-24會透過抑制背向牽引訊息netrin的受器UNC-5以避免DTC提早進行背向遷移。本研究計畫的目標是建立遠端細胞在第三幼蟲期進行背向遷移時的整合性調控網絡。我們將藉由生物資訊以及RNA干擾技術，找出遠端細胞在第三幼蟲期進行背向遷移新的調控分子；我們將在遺傳、分子生物以及生物化學等方面分析這些分子，並且建立這些分子間的作用路徑；最後，我們將進行電腦模擬來描述這些分子作用的動態模型。由於dre-1、daf-12、lin-29以及unc-5皆具有演化保守性，我們的研究將對於時間與空間的調控因子整合以控制適當的細胞遷移提供重要的知識。<br> Abstract: Cell migration is important for animal development and is an intensive research focus in the cellular and developmental biology. Proper cell migrations require integration of temporal and spatial information. Although many spatial regulators have been characterized, little is known about the temporal regulators and the mechanism that integrates both temporal and spatial regulation. Distal tip cells (DTCs) in C. elegans provide a paradigm for the studies of cell migration. A pair of DTCs are born at the ventral mid-body at the first larval stage (L1) and guide the extension of the two gonadal arms to migrate dorsalward in L3. F-box protein DRE-1, zinc-finger transcription factor LIN-29 and nuclear hormone receptor DAF-12 act redundantly to control the timing of DTC dorsalward turning, indicating a complex regulation mechanism including gene expression and protein degradation involved. We have identified a zinc-finger transcription factor DPY-24 that negatively regulates the dorsal guidance receptor UNC-5/netrin receptor to prevent DTC from precociously dorsalward turning. In addition, dpy-24 is genetically suppressed by dre-1, lin-29 or daf-12. The objective of this proposal is to establish an integrative regulatory circuit that controls DTC dorsal migration at the L3 stage. Specifically, we have the following aims. We will identify additional temporal and spatial regulators important for DTC dorsal migration at the L3 stage by in silico and genetic approaches. We will genetically, molecularly and biochemically characterize these regulators and establish their genetic and molecular interaction networks. Finally, we will model and simulate the behavior of the regulatory network by computation. Given the fact that dre-1, daf-12, lin-29 and unc-5 are evolutionarily conserved, this study will provide important knowledge for how the spatial and temporal regulators are integrated to control the proper cell migration in general.線蟲細胞遷移遠端細胞C. eleganscell migrationDTCs