The Role of Nonmuscle Myosins in Development

三种非肌肉肌球蛋白重链（NMHC）亚型II-A、II-B和II-C分别是三个不同基因MYH9、MYH10和MYH14的产物，是非肌肉肌球蛋白ii的主要亚基。具有NMHC II-A和II-C单氨基酸突变的人类家族已被描述为具有NMHC II-B点突变的小鼠。同源突变（人类NMHC II-A中的R702C、小鼠II-B中的R709C和人类II-C中的R726S）导致影响肾脏、血小板和白细胞（II-A）、心脏和大脑（II-B）以及内耳（II-C）的表型。通过同源重组，我们获得了NMHC II-C中R722C突变的小鼠。大约20%-30%的NMHC II-C突变小鼠在3-5月龄时发生淋巴增生性疾病。受影响的小鼠表现出明显的淋巴结病变，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累有关。受影响的突变小鼠胸腺表现为皮质萎缩，髓质增大，充满类似的细胞类型。一些小鼠表现为早期肾小球肾炎伴高细胞肾小球。通过FACS分析，来自受影响淋巴组织的淋巴细胞中有大量的细胞与B细胞标志物B220以及浆细胞标志物syndecan-1 （CD138）共同表达T细胞标志物CD3、CD4和TCRbeta。与未受影响小鼠的细胞相比，受影响小鼠的细胞对fasl诱导的凋亡具有抗性，这是由于细胞表面Fas （CD95）表达的缺失。由于未受影响和受影响的T细胞中Fas的总表达没有变化，突变细胞可能在Fas向细胞表面的运输方面存在缺陷，导致Fas抵抗，有助于CD3+B220+淋巴细胞的积累。异常Fas/FasL信号、涉及B220+ T细胞的淋巴增生和早期肾脏疾病之间的关联表明，受影响的小鼠患有一种以前未被识别的自身免疫性疾病。

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.