The Role of Nonmuscle Myosins in Development

三种非肌肌球蛋白重链（NMHC）亚型II-A、II-B和II-C分别是MYH 9、MYH 10和MYH 14三种不同基因的产物，是非肌肌球蛋白II的主要亚基。 在NMHC II-A和II-C中具有单个氨基酸突变的人类家族已经被描述为具有在NMHC II-B中具有点突变的小鼠。 同源突变（人NMHC II-A中的R702 C、鼠II-B中的R709 C和人II-C中的R726 S）导致影响肾脏、血小板和白细胞（II-A）、心脏和脑（II-B）以及内耳（II-C）的表型。 使用同源重组，我们产生了在NMHC II-C中具有R722 C突变的小鼠。 大约20%-30%的NMHC II-C突变小鼠在3-5个月大时发生淋巴组织增生性疾病。 受影响的小鼠表现出显著的淋巴结病，与正常结构的完全丧失和淋巴母细胞、浆细胞和组织细胞的积聚相关。 受影响的突变小鼠的胸腺表现出皮质萎缩和扩大的髓质充满了类似的细胞类型。 一些小鼠表现出早期肾小球肾炎，肾小球细胞增多。 通过FACS分析，来自受影响的淋巴组织的淋巴细胞具有大量共表达T细胞标志物CD 3、CD 4和TCR β以及B细胞标志物B220以及浆细胞标志物多配体蛋白聚糖-1（CD 138）的细胞。 与来自未受影响的小鼠的细胞相比，来自受影响的小鼠的细胞由于细胞表面Fas（CD 95）表达的丧失而对FasL诱导的细胞凋亡具有抗性。 由于在未受影响和受影响的T细胞中总Fas表达没有变化，突变细胞可能在Fas向细胞表面的转运方面存在缺陷，导致Fas抗性，这有助于CD 3 +B220+淋巴细胞的积累。 异常Fas/FasL信号传导、涉及B220+ T细胞的淋巴细胞增殖和早期肾脏疾病之间的关联表明，受影响的小鼠具有先前未被识别的自身免疫性疾病形式。

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.