The Role of Nonmuscle Myosins in Development and Disease

非肌肉肌球蛋白2A(NM 2A)的突变包括一系列统称为Myh9相关疾病(Myh9-RD)的异常，这些异常可包括白内障、肾小球硬化、大血小板减少和耳聋。我们之前建立了人类最常见的三种突变的小鼠模型：R702C、D1424N和E1841K。虽然纯合子R702C和D1424N突变对胚胎是致命的，但我们发现纯合子突变E1841K小鼠是存活的，但雄性而不是雌性小鼠是不育的。E1841K纯合子男性从出生后三周开始缩小睾丸大小，出现支持-支持细胞和支持-生殖细胞连接缺陷，导致血-睾丸屏障完整性丧失，生殖细胞过早丢失进入附睾。我们发现，在支持细胞中有条件地切除NM 2A的小鼠仍然具有生育能力，并且没有表现出E1841K纯合子男性中的任何缺陷，这表明NM 2A在支持细胞中是可有可无的，并且E1841K突变以一种不同于功能丧失的方式干扰精子发生。正在进行的在支持细胞中对NM 2A和NM 2B进行条件消融的小鼠的研究可能有助于澄清在混合双极细丝形成过程中，突变的NM 2A是否以显性负向的方式干扰正常的NM 2B。总之，这些结果确认了Myh9-RD小鼠模型中NM 2A突变的先前未报道的后果，并为进一步深入了解NM 2A在生殖细胞成熟和出生后睾丸发育过程中支持细胞中的作用提供了进一步的见解。

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.