Conditional ablation of nonmuscle myosin II-B delineates heart defects in adult mice.
BACKGROUND
Germline ablation of the cytoskeletal protein nonmuscle myosin II (NMII)-B results in embryonic lethality, with defects in both the brain and heart. Tissue-specific ablation of NMII-B by a Cre recombinase strategy should prevent embryonic lethality and permit study of the function of NMII-B in adult hearts.


OBJECTIVE
We sought to understand the function of NMII-B in adult mouse hearts and to see whether the brain defects found in germline-ablated mice influence cardiac development.


RESULTS
We used a loxP/Cre recombinase strategy to specifically ablate NMII-B in the brains or hearts of mice. Mice ablated for NMII-B in neural tissues die between postnatal day 12 and 22 without showing cardiac defects. Mice deficient in NMII-B only in cardiac myocytes (B(alphaMHC)/B(alphaMHC) mice) do not show brain defects. However, B(alphaMHC)/B(alphaMHC) mice display novel cardiac defects not seen in NMII-B germline-ablated mice. Most of the B(alphaMHC)/B(alphaMHC) mice are born with enlarged cardiac myocytes, some of which are multinucleated, reflecting a defect in cytokinesis. Between 6 to 10 months, they develop a cardiomyopathy that includes interstitial fibrosis and infiltration of the myocardium and pericardium with inflammatory cells. Four of 5 B(alphaMHC)/B(alphaMHC) hearts develop marked widening of intercalated discs.


CONCLUSIONS
By avoiding the embryonic lethality found in germline-ablated mice, we were able to study the function of NMII-B in adult mice and show that absence of NMII-B in cardiac myocytes results in cardiomyopathy in the adult heart. We also define a role for NMII-B in maintaining the integrity of intercalated discs.
Ma
Xuefei
X
Laboratory of Molecular Cardiology, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
Takeda
Kazuyo
K
Singh
Aman
A
Yu
Zu-Xi
ZX
Zerfas
Patricia
P
Blount
Anthony
A
Liu
Chengyu
C
Towbin
Jeffrey A
JA
Schneider
Michael D
MD
Adelstein
Robert S
RS
Wei
Qize
Q
D000367:Age Factors; D000818:Animals; D001921:Brain / Q000473:pathology; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D005804:Genes, Lethal; D018095:Germ-Line Mutation; D006321:Heart / Q000196:embryology; D006849:Hydrocephalus / Q000235:genetics / Q000473:pathology; D019426:Integrases / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D024501:Nonmuscle Myosin Type IIB / Q000235:genetics* / Q000378:metabolism*
D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C045073:Cre recombinase; D019426:Integrases; D024501:Nonmuscle Myosin Type IIB