Ablation and mutation of nonmuscle myosin heavy chain II-B results in a defect in cardiac myocyte cytokinesis.
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.
Takeda
Kazuyo
K
Laboratory of Molecular Cardiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md 20892-1762, USA.
Kishi
Hiroko
H
Ma
Xuefei
X
Yu
Zu-Xi
ZX
Adelstein
Robert S
RS
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D048429:Cell Size / Q000235:genetics; D002478:Cells, Cultured; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D005838:Genotype; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics*; D024501:Nonmuscle Myosin Type IIB
C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D003893:Desmin; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains; D001973:Bromodeoxyuridine