Uren D, Hwang H K, Hara Y, Takeda K, Kawamoto S, Tullio A N, Yu Z X, Ferrans V J, Tresser N, Grinberg A, Preston Y A, Adelstein R S
Laboratory of Molecular Cardiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1762, USA.
J Clin Invest. 2000 Mar;105(5):663-71. doi: 10.1172/JCI8199.
Complete ablation of nonmuscle myosin heavy chain II-B (NMHC-B) in mice resulted in cardiac and brain defects that were lethal during embryonic development or on the day of birth. In this paper, we report on the generation of mice with decreased amounts of NMHC-B. First, we generated B(DeltaI)/B(DeltaI) mice by replacing a neural-specific alternative exon with the PGK-Neo cassette. This resulted in decreased amounts of NMHC-B in all tissues, including a decrease of 88% in the heart and 65% in the brain compared with B(+)/B(+) tissues. B(DeltaI)/B(DeltaI) mice developed cardiac myocyte hypertrophy between 7 months and 11 months of age, at which time they reexpressed the cardiac beta-MHC. Serial sections of B(DeltaI)/B(DeltaI) brains showed abnormalities in neural cell migration and adhesion in the ventricular wall. Crossing B(DeltaI)/B(DeltaI) with B(+)/B(-) mice generated B(DeltaI)/B(-) mice, which showed a further decrease of approximately 55% in NMHC-B in the heart and brain compared with B(DeltaI)/B(DeltaI) mice. Five of 8 B(DeltaI)/B(-) mice were born with a membranous ventricular septal defect. Moreover, 5 of 5 B(DeltaI)/B(-) mice developed myocyte hypertrophy by 1 month; B(DeltaI)/B(-) mice also reexpressed the cardiac beta-MHC. More than 60% of B(DeltaI)/B(-) mice developed overt hydrocephalus and showed more severe defects in neural cell migration and adhesion than did B(DeltaI)/B(DeltaI) mice. These data on B(DeltaI)/B(DeltaI) and B(DeltaI)/B(-) mice demonstrate a gene dosage effect of the amount of NMHC-B on the severity and time of onset of the defects in the heart and brain.
小鼠中非肌肉肌球蛋白重链II - B（NMHC - B）的完全缺失导致心脏和大脑缺陷，这些缺陷在胚胎发育期间或出生当天是致命的。在本文中，我们报告了NMHC - B含量降低的小鼠的产生情况。首先，我们通过用PGK - Neo盒替换一个神经特异性可变外显子来产生B(DeltaI)/B(DeltaI)小鼠。这导致所有组织中NMHC - B的含量降低，与B(+)/B(+)组织相比，心脏中降低了88%，大脑中降低了65%。B(DeltaI)/B(DeltaI)小鼠在7个月至11个月大时出现心肌细胞肥大，此时它们重新表达心脏β - MHC。B(DeltaI)/B(DeltaI)大脑的连续切片显示心室壁神经细胞迁移和黏附异常。将B(DeltaI)/B(DeltaI)与B(+)/B(-)小鼠杂交产生了B(DeltaI)/B(-)小鼠，与B(DeltaI)/B(DeltaI)小鼠相比，其心脏和大脑中NMHC - B进一步降低了约55%。8只B(DeltaI)/B(-)小鼠中有5只出生时患有膜性室间隔缺损。此外，5只B(DeltaI)/B(-)小鼠中有5只在1个月时出现心肌细胞肥大；B(DeltaI)/B(-)小鼠也重新表达心脏β - MHC。超过60%的B(DeltaI)/B(-)小鼠出现明显的脑积水，并且与B(DeltaI)/B(DeltaI)小鼠相比，在神经细胞迁移和黏附方面表现出更严重的缺陷。这些关于B(DeltaI)/B(DeltaI)和B(DeltaI)/B(-)小鼠的数据证明了NMHC - B含量对心脏和大脑缺陷的严重程度和发病时间的基因剂量效应。
