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J. Biol. Chem., Vol. 282, Issue 30, 22102-22111, July 27, 2007

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Replacement of Nonmuscle Myosin II-B with II-A Rescues Brain but Not Cardiac Defects in Mice^*

Jianjun Bao¹, Xuefei Ma¹, Chengyu Liu, and Robert S. Adelstein²

From the Laboratory of Molecular Cardiology and Transgenic Core, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

The purpose of these studies was to learn whether one isoform of nonmuscle myosin II, specifically nonmuscle myosin II-A, could functionally replace a second one, nonmuscle myosin II-B, in mice. To accomplish this, we used homologous recombination to ablate nonmuscle myosin heavy chain (NMHC) II-B by inserting cDNA encoding green fluorescent protein (GFP)-NMHC II-A into the first coding exon of the Myh10 gene, thereby placing GFP-NMHC II-A under control of the endogenous II-B promoter. Similar to B^-/B^- mice, most B^a*/B^a* mice died late in embryonic development with structural cardiac defects and impaired cytokinesis of the cardiac myocytes. However, unlike B^-/B^- mice, 15 B^a*/B^a* mice of 172 F2 generation mice survived embryonic lethality but developed a dilated cardiomyopathy as adults. Surprisingly none of the B^a*/B^a* mice showed evidence for hydrocephalus that is always found in B^-/B^- mice. Rescue of this defect was due to proper localization and function of GFP-NMHC II-A in place of NMHC II-B in a cell-cell adhesion complex in the cells lining the spinal canal. Restoration of the integrity and adhesion of these cells prevents protrusion of the underlying cells into the spinal canal where they block circulation of the cerebral spinal fluid. However, abnormal migration of facial and pontine neurons found in NMHC II-B mutant and ablated mice persisted in B^a*/B^a* mice. Thus, although NMHC II-A can substitute for NMHC II-B to maintain integrity of the spinal canal, NMHC II-B plays an isoform-specific role during cytokinesis in cardiac myocytes and in migration of the facial and pontine neurons.

Received for publication, March 30, 2007 , and in revised form, May 17, 2007.

^* This work was supported by the Intramural Research Program of the NHLBI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

¹ To whom correspondence should be addressed. National Institutes of Health, Bldg. 10, Rm. 8N202, 10 Center Dr. MSC 1762, Bethesda, MD 20892-1762. Tel.: 301-496-1865; Fax: 301-402-1542; E-mail: adelster{at}nhlbi.nih.gov.

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