Cellular defects resulting from disease-related myosin II mutations in Drosophila Journal Article
| Authors: | Kasza, K. E.; Supriyatno, S.; Zallen, J. A. |
| Article Title: | Cellular defects resulting from disease-related myosin II mutations in Drosophila |
| Abstract: | The nonmuscle myosin II motor protein produces forces that are essential to driving the cell movements and cell shape changes that generate tissue structure. Mutations in myosin II that are associated with human diseases are predicted to disrupt critical aspects of myosin function, but the mechanisms that translate altered myosin activity into specific changes in tissue organization and physiology are not well understood. Here we use the Drosophila embryo to model human disease mutations that affect myosin motor activity. Using in vivo imaging and biophysical analysis, we show that engineering human MYH9-related disease mutations into Drosophila myosin II produces motors with altered organization and dynamics that fail to drive rapid cell movements, resulting in defects in epithelial morphogenesis. In embryos that express the Drosophila myosin motor variants R707C or N98K and have reduced levels of wild-type myosin, myosin motors are correctly planar polarized and generate anisotropic contractile tension in the tissue. However, expression of these motor variants is associated with a cellular-scale reduction in the speed of cell intercalation, resulting in a failure to promote full elongation of the body axis. In addition, these myosin motor variants display slowed turnover and aberrant aggregation at the cell cortex, indicating that mutations in the motor domain influence mesoscale properties of myosin organization and dynamics. These results demonstrate that disease-associated mutations in the myosin II motor domain disrupt specific aspects of myosin localization and activity during cell intercalation, linking molecular changes in myosin activity to defects in tissue morphogenesis. © 2019 National Academy of Sciences. All rights reserved. |
| Keywords: | controlled study; protein expression; mutation; nonhuman; protein domain; protein function; protein localization; gene; cell function; embryo; cell motion; drosophila; morphogenesis; in vivo study; cell aggregation; epithelium; cell interaction; myosin ii; muscle contractility; biophysics; intercalation complex; epithelia; priority journal; article; contractility; myh9 gene |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 116 |
| Issue: | 44 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2019-10-29 |
| Start Page: | 22205 |
| End Page: | 22211 |
| Language: | English |
| DOI: | 10.1073/pnas.1909227116 |
| PUBMED: | 31615886 |
| PROVIDER: | scopus |
| PMCID: | PMC6825282 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work