The Role of Nonmuscle Myosins in Development

Heart, Lung, And Blood Institute

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Abstract

Three nonmuscle myosin heavy chain (NMHC) isoforms, II-A, II-B and II-C, which are the products of three different genes, MYH9, MYH10 and MYH14, respectively, are the major subunits of nonmuscle myosin IIs. Human families with single amino acid mutations in NMHC II-A and II-C have been described as have mice generated with a point mutation in NMHC II-B. Homologous mutations (R702C in human NMHC II-A, R709C in murine II-B, and R726S in human II-C) result in phenotypes affecting kidneys, platelets and leucocytes (II-A), heart and brain (II-B), and the inner ear (II-C). Using homologous recombination, we generated mice with the R722C mutation in NMHC II-C. Approximately 20%-30% of NMHC II-C mutant mice develop a lymphoproliferative disease at 3-5 months of age. Affected mice exhibit striking lymphadenopathy associated with complete loss of normal architecture and accumulations of lymphoblasts, plasma cells and histiocytes. Thymuses of affected mutant mice exhibit cortical atrophy and enlarged medullae filled with similar cell types. Some mice exhibit early glomerulonephritis with hypercellular glomeruli. By FACS analysis, lymphocytes from affected lymphoid tissues have large numbers of cells that co-express T cell markers, CD3, CD4 and TCRbeta together with the B cell marker, B220, in addition to the plasma cell marker, syndecan-1 (CD138). Compared to cells from unaffected mice, cells from affected mice are resistant to FasL-induced apoptosis due to a loss of Fas (CD95) expression at the cell surface. Since there is no change in total Fas expression in the unaffected and affected T cells, the mutant cells may have a defect in transport of Fas to the cell surface, resulting in Fas resistance that contributes to the accumulation of CD3+B220+ lymphocytes. The association between abnormal Fas/FasL signaling, lymphoproliferation involving B220+ T cells and early renal disease suggests that the affected mice have a previously unrecognized form of autoimmune disease.