Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, and Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, and Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Dev Cell. 2019 Oct 7;51(1):89-98.e4. doi: 10.1016/j.devcel.2019.08.002. Epub 2019 Aug 29.
We previously identified a unique population of interstitial muscle progenitors, marked by expression of the Twist2 transcription factor, which fuses specifically to type IIb/x fast-twitch myofibers. Tw2 progenitors are distinct from satellite cells, a muscle progenitor that expresses Pax7 and contributes to all myofiber types. Through RNA sequencing and immunofluorescence, we identify the membrane receptor, Nrp1, as a marker of Tw2 cells but not Pax7 cells. We also found that Sema3a, a chemorepellent ligand for Nrp1, is expressed by type I and IIa myofibers but not IIb myofibers. Using stripe migration assays, chimeric cell-cell fusion assays, and a Sema3a transgenic mouse model, we identify Sema3a-Nrp1 signaling as a major mechanism for Tw2 cell fiber-type specificity. Our findings reveal an extracellular signaling mechanism whereby a cell-surface receptor for a chemorepellent confers specificity of intercellular fusion of a specific muscle progenitor with its target tissue.
我们之前鉴定出一种独特的间质肌肉祖细胞群体，其特征是表达 Twist2 转录因子，该转录因子特异性融合到 IIb/x 型快肌纤维。Tw2 祖细胞与卫星细胞不同，卫星细胞是一种表达 Pax7 的肌肉祖细胞，可贡献于所有肌纤维类型。通过 RNA 测序和免疫荧光，我们将膜受体 Nrp1 鉴定为 Tw2 细胞的标志物，但不是 Pax7 细胞的标志物。我们还发现，Nrp1 的趋化抑制配体 Sema3a 由 I 型和 IIa 型肌纤维表达，但不表达于 IIb 型肌纤维。通过条纹迁移测定、嵌合细胞-细胞融合测定和 Sema3a 转基因小鼠模型，我们确定 Sema3a-Nrp1 信号是 Tw2 细胞纤维类型特异性的主要机制。我们的发现揭示了一种细胞外信号机制，其中趋化抑制性配体的细胞表面受体赋予特定的肌肉祖细胞与其靶组织之间细胞间融合的特异性。
