Mutations in non-muscle myosin 2A disrupt the actomyosin cytoskeleton in Sertoli cells and cause male infertility.

Mutations in non-muscle myosin 2A (NM2A) encompass a wide spectrum of anomalies collectively known as MYH9-Related Disease (MYH9-RD) in humans that can include macrothrombocytopenia, glomerulosclerosis, deafness, and cataracts. 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. However the homozygous male, but not female, mice were infertile. Here, we report that these mice have reduced testis size and defects in actin-associated junctions in Sertoli cells, resulting in inability to form the blood-testis barrier and premature germ cell loss. Moreover, compound double heterozygous (R702C/E1841K and D1424/E1841K) males show the same abnormalities in testes as E1841K homozygous males. Conditional ablation of either NM2A or NM2B alone in Sertoli cells has no effect on fertility and testis size, however deletion of both NM2A and NM2B in Sertoli cells results in infertility. Isolation of mutant E1841K Sertoli cells reveals decreased NM2A and F-actin colocalization and thicker NM2A filaments. Furthermore, AE1841K/AE1841K and double knockout Sertoli cells demonstrate microtubule disorganization and increased tubulin acetylation, suggesting defects in the microtubule cytoskeleton. Together, these results demonstrate that NM2A and 2B paralogs play redundant roles in Sertoli cells and are essential for testes development and normal fertility. •Human disease-causing mutations in Myh9 cause abnormalities in Sertoli cells, BTB defects, and infertility in male mice. •Mutant Sertoli cells are characterized by abnormal morphology and cytoskeletal structures. •Deletion of either NM2A or NM2B in Sertoli cells does not affect fertility, demonstrating redundant roles for NM2 paralogs. •Deletion of both NM2A and NM2B recapitulates these defects suggesting that mutant NM2A interferes with the function of NM2B. [ABSTRACT FROM AUTHOR]