The Role of Nonmuscle Myosins in Development and Disease

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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