Ablation and mutation of nonmuscle myosin heavy chain II-B results in a defect in cardiac myocyte cytokinesis
Ablation and mutation of nonmuscle myosin heavy chain II-B results in a defect in cardiac myocyte cytokinesis
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DOI：
10.1161/01.res.0000089256.00309.cb
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发表时间：
2003-08-22
影响因子：
20.1
通讯作者：
Adelstein, RS
中科院分区：
文献类型：
--
作者：
Takeda, K;Kishi, H;Adelstein, RS
我们在非肌肉肌球蛋白重链II-B （NMHC II-B）消融小鼠中发现了一种新的心肌细胞扩大形式，基于细胞分裂的部分失败。与大多数细胞相比，心肌细胞缺乏NMHC II-A， NMHC II-B的消融导致胚胎14.5天（E14.5）心肌细胞比对照小鼠（B+/B-和B+/B+）少70%。此外，B-/B-心肌细胞在E12.5时双核明显增加，反映了在没有细胞分裂的情况下发生了核分裂。在编码NMHC II-B基因的单氨基酸突变（R709C）的半胚、纯合子小鼠中也发现双核和细胞大小的增加。B-/B-心脏和纯合突变心脏中的非肌细胞均含有NMHC II-A，不表现出上述任何一种异常。与对照组相比，E14.5组的B-/B-心肌细胞显示溴脱氧尿苷（BrdU）标记指数下降，与心肌细胞增殖减少一致。这种降低的BrdU标记在心脏非肌细胞中未见。除了这些变化，B-/B-小鼠和纯合突变小鼠都显示出周期蛋白D2和D3的增加，反映了细胞周期早期步骤的异常。而完全消融NMHC II-B的心肌细胞显示增大和双核，在心脏中表达少量正常数量的野生型NMHC II-B的小鼠没有表现出这些异常。
We have identified a novel form of cardiac myocyte enlargement in nonmuscle myosin heavy chain II-B (NMHC II-B) ablated mice, based on a partial failure in cytokinesis. In contrast to most cells, cardiac myocytes lack NMHC II-A, and ablation of NMHC II-B results in a heart with 70% fewer myocytes at embryonic day 14.5 (E14.5) than control mice (B+/B- and B+/B+). In addition, B-/B- cardiac myocytes show a marked increase in binucleation at E12.5, reflecting the occurrence of karyokinesis in the absence of cytokinesis. An increase in binucleation and cell size is also found in hypomorphic, homozygous mice harboring a single amino acid mutation (R709C) in the gene encoding NMHC II-B. The nonmyocytes in B-/B- hearts and homozygous mutant hearts, all of which contain NMHC II-A, do not show either of these abnormalities. B-/B- cardiac myocytes at E14.5 show a decreased bromodeoxyuridine (BrdU) labeling index compared with controls, consistent with the decrease in myocyte proliferation. This decreased BrdU labeling is not seen in nonmyocyte cells in the heart. In addition to these changes, both B-/B- mice as well as homozygous mutated mice show an increase in cyclin D2 and D3 reflecting an abnormality in earlier steps in the cell cycle. Whereas cardiac myocytes completely ablated for NMHC II-B show enlargement and binucleation, mice expressing as little as 6% of the normal amount of wild-type NMHC II-B in the heart do not show these abnormalities.