Lian Yen-Ling, Chen Kuan-Wei, Chou Yu-Ting, Ke Ting-Ling, Chen Bi-Chang, Lin Yu-Chun, Chen Linyi
Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan.
Research Center for Applied Sciences, Academia Sinica, Taipei 11529, Taiwan.
J Cell Sci. 2020 Apr 28;133(8):jcs240325. doi: 10.1242/jcs.240325.
Myoblast fusion is required for myotube formation during myogenesis, and defects in myoblast differentiation and fusion have been implicated in a number of diseases, including human rhabdomyosarcoma. Although transcriptional regulation of the myogenic program has been studied extensively, the mechanisms controlling myoblast fusion remain largely unknown. This study identified and characterized the dynamics of a distinct class of blebs, termed bubbling blebs, which are smaller than those that participate in migration. The formation of these bubbling blebs occurred during differentiation and decreased alongside a decline in phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the plasma membrane before myoblast fusion. In a human rhabdomyosarcoma-derived (RD) cell line that exhibits strong blebbing dynamics and myoblast fusion defects, PIP3 was constitutively abundant on the membrane during myogenesis. Targeting phosphatase and tensin homolog (PTEN) to the plasma membrane reduced PIP3 levels, inhibited bubbling blebs and rescued myoblast fusion defects in RD cells. These findings highlight the differential distribution and crucial role of PIP3 during myoblast fusion and reveal a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma.
在肌生成过程中，成肌细胞融合是肌管形成所必需的，而成肌细胞分化和融合缺陷与包括人类横纹肌肉瘤在内的多种疾病有关。尽管对肌生成程序的转录调控已进行了广泛研究，但控制成肌细胞融合的机制仍 largely 未知。本研究鉴定并表征了一类独特的气泡，称为气泡状气泡，其比参与迁移的气泡小。这些气泡状气泡的形成发生在分化过程中，并在成肌细胞融合前随着质膜上磷脂酰肌醇 -（3,4,5）-三磷酸（PIP3）的下降而减少。在具有强烈气泡动态和成肌细胞融合缺陷的人横纹肌肉瘤衍生（RD）细胞系中，PIP3 在肌生成过程中在膜上持续丰富。将磷酸酶和张力蛋白同源物（PTEN）靶向质膜可降低 PIP3 水平，抑制气泡状气泡并挽救 RD 细胞中的成肌细胞融合缺陷。这些发现突出了 PIP3 在成肌细胞融合过程中的差异分布和关键作用，并揭示了人类横纹肌肉瘤中肌生成缺陷的一种新机制。
