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Title: | 肌原細胞融合時期Tks5在侵襲體形成中扮演之角色 The Role of Tks5 in Invadosome Formation during Myoblast Fusion |
Authors: | Mei-Chun Chuang 莊梅均 |
Advisor: | 劉雅雯(Ya-Wen Liu) |
Keyword: | 肌肉新生,Dyn2,Tks5亞型轉換,侵襲體,肌動蛋白束硬度, myogenesis,Dynamin-2,Tks5 isoform switching,invadosome,actin bundle rigidity, |
Publication Year : | 2019 |
Degree: | 博士 |
Abstract: | 多細胞核的骨骼肌纖維是由肌原母細胞的分化及相互融合而成。目前研究普遍認為細胞骨架-肌動蛋白是肌原母細胞間融合的主要推動力。然而,肌動蛋白在肌原母細胞內是如何被組織調控;以及肌原母細胞是如何具有融合的能力還不甚清楚。本研究指出:肌原母細胞會利用一個主要成分為肌動蛋白的結構,侵襲體,去推動細胞間的融合。隨著細胞分化,肌原母細胞因關鍵的侵襲體銜接蛋白-Tks5的亞型轉換而具有形成侵襲體的能力。Tks5藉由直接與另一個侵襲體蛋白Dynamin-2結合將其聚集到肌原母細胞融合之處,並調控Dynamin-2纏繞到肌動蛋白上的結構,進而增強了Dynamin-2-肌動蛋白束以及侵襲體的物理硬度。綜合以上結果,我們的發現為肌原母細胞間融合的分子機轉帶來曙光,並解開Tks5與Dynamin-2在侵襲體中調控肌動蛋白絲而促使細胞膜融合的新穎結構性功能。 The multi-nucleated skeletal muscle fibers arise from the fusion of differentiated myoblasts. While the actin cytoskeleton is known as the driving force for myoblast fusion, how exactly actin is organized in fusing myoblasts and by what means myoblast become fusion competent are poorly understood. In this study, we report that myoblast utilizes an actin-based structure, invadosome, to propel cell-cell fusion. Upon differentiation, myoblasts acquire the ability to form invadosome through the induction of a critical invadosome scaffold protein, the Tyrosine kinase substrate with 5 SH3 domain (Tks5). Tks5 directly interacts with and recruits another invadosome component protein, Dynamin-2 (Dyn2), to the invadosome and regulates Dyn2 assembly around actin filaments. This regulation strengthens the stiffness of Dynamin-actin bundles in vitro and invadosome in vivo. Together, our findings shed light on the molecular mechanism of myogenic fusion machinery and revealed a novel structural function for Tks5 and Dynamin-2 in organizing actin filaments in the invadosome to drive membrane fusion. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74427 |
DOI: | 10.6342/NTU201902920 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 分子醫學研究所 |
Files in This Item:
File | Size | Format | |
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ntu-108-1.pdf Restricted Access | 39.73 MB | Adobe PDF |
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