The Role of Nonmuscle Myosin 2B In Vivo

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Summary Mammals including humans and mice express three nonmuscle myosin 2 paralogs (NM 2A, 2B, and 2C). Two alternatively spliced exons, each at the ATP and/or at actin binding regions, can be incorporated into the heavy chains of NM 2B (B1 and B2 inserts) and 2C (C1 and C2 inserts), but not into NM 2A. Mice ablated for NM 2A die very early, at E6.5, before gastrulation with defects in visceral endoderm formation. Mice ablated for NM 2B die by E14.5 with major defects in the heart and brain, while mice ablated for NM 2C survive to adulthood showing no obvious abnormalities. To understand the specific roles of NM 2A in early mouse development, we have generated genetically swapped mice where NM 2A expression was replaced either by the non-inserted isoform of NM 2B or the inserted isoform of NM C1 (the two most widely expressed isoforms for NM 2B and 2C respectively in mammals) under the endogenous NM 2A promoter. We have previously demonstrated that mice expressing NM 2B in place of NM 2A survive beyond gastrulation but die by E12.5 with major defects in placenta formation. Here we report studies from mice where NM 2A is substituted for by GFP-fused, NM 2C1-GFP (AC1*gfp/AC1*gfp). NM 2C1, similarly to NM 2B, can substitute for 2A in supporting normal functional visceral endoderm formation and mouse embryonic development beyond gastrulation. However, NM 2C1, similarly to NM 2B, cannot support normal placental vascular formation. AC1*gfp/AC1*gfp embryos die by E10.5 with a poorly developed, un-expanded placental labyrinth which lacks intermingling of the fetal and maternal blood vasculatures. The defect in vascular formation is further confirmed in allantois explants from AC1*gfp/AC1*gfp embryos. Additionally, each NM 2 paralog has overlapping as well as a unique cellular localization in migrating cells. Thus, NM 2A is essential for normal placental vascular formation during mouse embryonic development. We attribute this to a specific role for NM 2A in regulating the actomyosin cytoskeleton, the formation of focal adhesions, and for providing persistence in cell migration. In contrast, a role of NM 2A in maintaining visceral endodermal cell-cell adhesions and its function in supporting gastrulation, can be replaced by either NM 2B or NM 2C1.