Tan Dandan, Liu Yidan, Luo Huaxia, Shen Qiang, Long Xingbo, Xu Luzheng, Liu Jieyu, Zhong Nanbert A, Zhang Hong, Xiong Hui
Department of Pediatrics, Peking University First Hospital, Beijing, China.
Department of Neurology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Elife. 2025 Sep 17;13:RP94288. doi: 10.7554/eLife.94288.
Our understanding of the molecular pathogenesis of -related muscular dystrophy (-MD) requires improving. Here, we report the phenotype, neuropathology, and transcriptomics data (scRNA-seq and bulk RNA-seq) of a new knockout mouse (dy/dy) which was created based on the human -MD mutation hotspot region using CRISPR-Cas9. The dy/dy mice presented a severe phenotype with muscular dystrophy. Mouse brain scRNA-seq showed that gene was expressed predominantly and specifically in vascular and leptomeningeal fibroblasts and vascular smooth muscle cells, and weakly in astrocytes in wild-type mouse. Laminin α2 expression on the cortical surface was observed with immunofluorescence. In dy/dy, expression was decreased in those cell types, which might be associated with the disruption of gliovascular basal lamina assembly. Additionally, transcriptomic investigation of muscles showed 2020 differentially expressed genes, mainly associated with the impaired muscle cytoskeleton and development. In summary, this study provided potentially useful information for understanding the molecular pathogenesis of -MD.
我们对相关肌营养不良症（-MD）分子发病机制的理解有待提高。在此，我们报告了一种新的基因敲除小鼠（dy/dy）的表型、神经病理学和转录组学数据（单细胞RNA测序和批量RNA测序），该小鼠是使用CRISPR-Cas9基于人类-MD突变热点区域创建的。dy/dy小鼠表现出严重的肌营养不良表型。小鼠脑单细胞RNA测序表明，在野生型小鼠中，基因主要在血管和软脑膜成纤维细胞以及血管平滑肌细胞中特异性表达，在星形胶质细胞中表达较弱。通过免疫荧光观察到皮质表面层粘连蛋白α2的表达。在dy/dy小鼠中，这些细胞类型中的表达降低，这可能与神经血管基底层组装的破坏有关。此外，对肌肉的转录组学研究显示有2020个差异表达基因，主要与受损的肌肉细胞骨架和发育有关。总之，本研究为理解-MD的分子发病机制提供了潜在有用的信息。
