Gene dosage affects the cardiac and brain phenotype in nonmuscle myosin II-B–depleted mice

Abstract

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^ΔI/B^ΔI 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^ΔI/B^ΔI mice developed cardiac myocyte hypertrophy between 7 months and 11 months of age, at which time they reexpressed the cardiac β-MHC. Serial sections of B^ΔI/B^ΔI brains showed abnormalities in neural cell migration and adhesion in the ventricular wall. Crossing B^ΔI/B^ΔI with B⁺/B^– mice generated B^ΔI/B^– mice, which showed a further decrease of approximately 55% in NMHC-B in the heart and brain compared with B^ΔI/B^ΔI mice. Five of 8 B^ΔI/B^– mice were born with a membranous ventricular septal defect. Moreover, 5 of 5 B^ΔI/B^– mice developed myocyte hypertrophy by 1 month; B^ΔI/B^– mice also reexpressed the cardiac β-MHC. More than 60% of B^ΔI/B^– mice developed overt hydrocephalus and showed more severe defects in neural cell migration and adhesion than did B^ΔI/B^ΔI mice. These data on B^ΔI/B^ΔI and B^ΔI/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.