Mice ablated for nonmuscle myosin heavy chain (NMHC) II-B develop major structural abnormalities in their hearts and brains and die between E14 and their birth day. These abnormalities include a ventricular septal defect (VSD), mislocation of the aorta and a defect in cytokinesis involving the cardiac myocytes, which are enlarged and binucleated. The brain defects include an abnormal migration of specific groups of neurons (facial, pontine and cerebellar) and a severe hydrocephalus. Cardiac myocytes are unique in that they do not express NMHC II-A, and neuronal cells are enriched for NMHC II-B, which could explain the phenotype observed. The purpose of the present experiments was to see whether expression of NMHC II-A could rescue the defects due to the loss of NMHC II-B. We used GFP-tagged human NMHC II-A cDNA to ablate NMHC II-B by inserting it into the first coding exon, thus placing GFP-NMHC II-A under control of the endogenous II-B promoter. Interestingly, 20% of the B-A*/B-A* (A* = human GFP-NMHC II-A) mice survived beyond 3 months and appeared healthy and were fertile. These mice showed no evidence for a hydrocephalus nor did they manifest obvious cardiac defects. They did show a defect in facial neuron migration. Immunoblot and immunofluorescence analysis showed no expression of NMHC II-B in the heart, lung and brain, but demonstrated significant expression of GFP-NMHC II-A. Analysis of mice between E12 and birth revealed that some of the hearts had an increase in binucleated cells, but no evidence for myocyte enlargement. At least one mouse had a VSD. Thus, it appears that NMHC II-A expression can rescue some, but not all II-B ablated mice. The difference between the mice that survive and those that die is under study.
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