NONMUSCLE MYOSIN II-A PLAYS A ROLE IN SPERM DEVELOPMENT
Connie Lerma Cervantes1, Keizo Tokuhiro1, Neal Billington1, Aibing Wang1, Yingfan Zhang1, Mary Anne Conti1, Michael Kelley2, Matthew Daniels1, James Sellers1, Jurrien Dean1, Robert S. Adelstein1.
1National Heart, Lung, and Blood Institute, Bethesda, MD, 2Duke University, Durham, NC.
Sperm head shaping is dependent upon the constriction of F-actin found in the Sertoli cells and a cytoskeletal plate known as the acroplaxome and its marginal ring. Furthermore, the presence of the acroplaxome is necessary for the anchoring of the acrosomal vesicle to the nuclear lamina. These differentiation processes as well as the coupling of the tail to the spermatid head are known as spermiogenesis. We have studied a mouse line with a mutation, E1841K, found in human MYH9-related disease. In addition to modeling macrothrombocytopenia, glomerulosclerosis, cataracts, and deafness (MYH9 RD), male mice homozygous for the mutation (AE1841K/AE1841K) are infertile. Histological analyses reveal severe sperm defects during spermiogenesis. Importantly, transmission electron microscopy uncovers aberrant spermatid elongation whereby spermatids fail to correctly extend and condense the acrosome. The acroplaxome shows an irregular wavy-like appearance while the elongated spermatids fail to couple the developing tail to the spermatid. Immunofluorescence confocal microscopy of developing spermatids shows localization of nonmuscle myosin II-A (NM II-A) to the marginal ring of the acroplaxome. In vitro experiments using baculovirus-expressed NM II show abnormal filament formation of the AE1841K/AE1841K myosin. The mutant filaments formed by the AE1841K/AE1841K myosin are longer and tend to form aggregates (A+/A+ = 314 +/- 28 nm, AEK/AEK = 372 +/- 94 nm length). The results suggest that the abnormal NM II-A filaments may form a debilitating marginal ring, which leads to abnormal sperm head shaping. Collectively, these observations suggest a previously unknown role for NM II-A in male fertility.