PDF(Pubmed)
Abstract：
Mutations in cysteine and glycine-rich protein 3 (CSRP3)/muscle LIM protein (MLP), a key regulator of striated muscle function, have been linked to hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in patients. However, the roles of CSRP3 in heart development and regeneration are not completely understood. In this study, we characterized a novel zebrafish gene-trap line, gSAIzGFFM218A, which harbors an insertion in the csrp3 genomic locus, heterozygous fish served as a csrp3 expression reporter line and homozygous fish served as a csrp3 mutant line. We discovered that csrp3 is specifically expressed in larval ventricular cardiomyocytes (CMs) and that csrp3 deficiency leads to excessive trabeculation, a common feature of CSRP3-related HCM and DCM. We further revealed that csrp3 expression increased in response to different cardiac injuries and was regulated by several signaling pathways vital for heart regeneration. Csrp3 deficiency impeded zebrafish heart regeneration by impairing CM dedifferentiation, hindering sarcomere reassembly, and reducing CM proliferation while aggravating apoptosis. Csrp3 overexpression promoted CM proliferation after injury and ameliorated the impairment of ventricle regeneration caused by pharmacological inhibition of multiple signaling pathways. Our study highlights the critical role of Csrp3 in both zebrafish heart development and regeneration, and provides a valuable animal model for further functional exploration that will shed light on the molecular pathogenesis of CSRP3-related human cardiac diseases.
摘要：
半胱氨酸和富含甘氨酸的蛋白3（CSRP3）/肌肉LIM蛋白（MLP）的突变，横纹肌功能的关键调节器，已与患者的肥厚型心肌病（HCM）和扩张型心肌病（DCM）有关。然而,CSRP3在心脏发育和再生中的作用尚不完全清楚。在这项研究中,我们表征了一种新的斑马鱼基因陷阱系，gSAIzGFFM218A,在csrp3基因组基因座中插入，杂合子鱼用作csrp3表达报告系，纯合子鱼用作csrp3突变系。我们发现csrp3在幼虫心室心肌细胞（CMs）中特异性表达，并且csrp3缺乏导致过度的小梁形成，CSRP3相关的HCM和DCM的共同特征。我们进一步揭示了csrp3表达在不同心脏损伤的反应中增加，并受到对心脏再生至关重要的几种信号通路的调节。Csrp3缺乏通过损害CM去分化来阻碍斑马鱼心脏再生，阻碍肌节重组，减少CM增殖，加重细胞凋亡。Csrp3过表达促进损伤后CM的增殖，并改善由多种信号通路的药理抑制引起的心室再生障碍。我们的研究强调了Csrp3在斑马鱼心脏发育和再生中的关键作用，并为进一步的功能探索提供了有价值的动物模型，将阐明CSRP3相关人类心脏病的分子发病机制。
