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）的广泛的异常，其可以包括白内障、肾小球硬化症、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尺寸减小，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到附睾中。我们发现支持细胞中NM 2A的条件性消融小鼠保持生育能力，并且没有显示在E1841 K纯合子雄性中看到的缺陷，这表明NM 2A在支持细胞中是缺失的，并且E1841 K突变以不同于功能丧失的模式干扰精子发生。正在进行的研究利用小鼠条件性消融支持细胞中的NM 2A和NM 2B可能有助于澄清突变NM 2A是否干扰正常NM 2B在形成混合双极丝的显性负性方式。总之，这些结果确定了MYH 9-RD小鼠模型中NM 2A突变的先前未报告的结果，并进一步了解NM 2A在生殖细胞成熟和出生后睾丸发育过程中在支持细胞中的作用。

Mutations in non-muscle myosin 2A (NM 2A) 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 are 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 into the epididymis. We found that mice conditionally ablated for NM 2A in Sertoli cells remain fertile and display none of the defects seen in E1841K homozygote males, suggesting that NM 2A is dispensable in Sertoli cells, and that the E1841K mutation interferes with spermatogenesis in a mode different from loss-of-function. Ongoing studies utilizing mice conditionally ablated for both NM 2A and NM 2B in Sertoli cells may help clarify whether mutant NM 2A interferes with normal NM 2B in a dominant negative fashion during the formation of mixed bipolar filaments. Together, these results identify a previously unreported consequence of NM 2A mutations in MYH9-RD mouse models and provide further insight into the role of NM 2A in Sertoli cells during germ cell maturation and postnatal testes development.