The Role of Nonmuscle Myosin II-B in Brain Development

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We generated mice harboring a single amino acid mutation in the motor domain of nonmuscle myosin heavy chain II-B (NMHC II-B). Homozygous mutant mice had an abnormal gait and difficulties in maintaining balance. Consistent with their motor defects, the mutant mice displayed an abnormal pattern of cerebellar foliation. Analysis of the brains of homozygous mutant mice showed significant defects in neuronal migration involving granule cells in the cerebellum, the facial neurons and the anterior extramural precerebellar migratory stream. A high level of NMHC II-B expression in these neurons suggests an important role for this molecule during their migration in the developing brain. Increased phosphorylation of the myosin regulatory light chain in migrating, compared to stationary pontine neurons supports an active role for myosin in regulating their migration. These studies demonstrate that NMHC II-B is particularly important for normal migration of distinct groups of neurons during mouse brain development. We are presently characterizing mutant mice which show the same level of expression as wild-types following removal of the Neo-R cassette. These mice are of interest since, in contrast to our findings in mice with a null mutation for NMHC II-B, about one-half of the heterozygous mutant mice developed umbilical and diaphragmatic hernias, and died shortly after the birth. The remainder of the heterozygous mice survived to adulthood and were fertile, although subtle defects in closure of the umbilical area and diaphragm development were still observed. Homozygous mice died at approximately embryonic day 16.5, displaying abnormalities involving the ventral body wall, diaphragm, heart and brain. All these mice show severe defects in midline fusion with a large hernia containing most of the liver and intestine, a split sternum and externalized heart. The diaphragm of the mutant mice was very thin. The mutant heart had both the aorta and pulmonary artery emanating from the right ventricle, a ventricular septal defect, abnormal development of the cardiac cushions, and a much thinner compact zone of both the ventricle and atrial walls compared to the wild-type littermate. Similar to the hypomorphic mutant mice, which retain the Neo-cassette in the mutant alleles, hydrocephalus and abnormal migration of certain groups of neurons were also seen in these mice. Unlike the hypomorphic mutant mouse however, no obvious defects in cytokinesis of the cardiomyocytes in the embryonic heart were seen in the nonhypomorphic R709C mutant mice.