The Role of Nonmuscle Myosins in Development and Disease

非肌肉肌球蛋白2A（NM 2A）的突变包括统称为MYH 9相关疾病（MYH 9-RD）的广泛异常，其可以包括白内障、肾小球硬化、巨血小板减少症和耳聋。我们之前创建了人类中最常见的三种突变的小鼠模型：R702 C，D1424 N和E1841 K。虽然纯合子R702 C和D1424 N突变是胚胎致死的，但我们发现纯合子突变E1841 K小鼠是可行的，但雄性而不是雌性小鼠是不育的。E1841 K纯合子男性从出生后三周开始睾丸大小减少，支持-支持和支持-生殖细胞连接缺陷，导致血-睾丸屏障完整性丧失和生殖细胞过早丢失。此外，突变体睾丸和支持细胞中微管蛋白的过度乙酰化与肌动蛋白紊乱相关，表明肌动球蛋白微管动力学的潜在破坏。在培养的原代支持细胞中的NM 2A和微管蛋白表达的分析表明，突变细胞具有异常的NM 2A分布，形成较厚的细丝，并且不能协调NM 2A和微管蛋白的空间定位。总之，这些结果确定了MYH 9-RD小鼠模型中NM 2A突变的先前未报道的特征，并提供了对NM 2A在支持细胞中调节肌动球蛋白微管动力学以支持生殖细胞成熟的作用的进一步了解

Mutations in non-muscle myosin 2A (NM2A) encompass a wide spectrum of anomalies collectively known as MYH9-Related Disease (MYH9-RD) that can include cataracts, glomerulosclerosis, macrothrombocytopenia, and deafness. We previously created mouse models of the three mutations most frequently found in humans: R702C, D1424N, and E1841K. While homozygous R702C and D1424N mutations are embryonic lethal, we found homozygous mutant E1841K mice to be viable, but male, and not female, mice were infertile. E1841K homozygous males have reduced testes size starting from three weeks after birth with defects in Sertoli-Sertoli and Sertoli-germ cell junctions, resulting in loss of blood-testis barrier integrity and premature germ cell loss. Furthermore, excessive acetylation of tubulin in mutant testes and Sertoli cells are correlated with actin disorganization indicating potential disruptions in actomyosin-microtubule dynamics. Analysis of NM2A and tubulin expression in primary Sertoli cells in culture shows that mutant cells have an abnormal NM2A distribution, form thicker filaments, and fail to coordinate spatial localization of NM2A and tubulin. Together, these results identify a previously unreported characteristic of NM2A mutations in MYH9-RD mouse models and provide further insight into the role of NM2A in regulating actomyosin-microtubule dynamics in Sertoli cells to support germ cell maturation