Variant forms of human MYH9 introduced into flies as part of study related to understanding muscle-related diseases

Kasza KE, Supriyatno S, Zallen JA. Cellular defects resulting from disease-related myosin II mutations in Drosophila. Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22205-22211. doi: 10.1073/pnas.1909227116. Epub 2019 Oct 15. PubMed PMID: 31615886; PubMed Central PMCID: PMC6825282.

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."

Fly model provides "first animal models for myosin-based Freeman-Sheldon syndrome (FSS)"

Rao DS, Kronert WA, Guo Y, Hsu KH, Sarsoza F, Bernstein SI. Reductions in ATPase activity, actin sliding velocity, and myofibril stability yield muscle dysfunction in Drosophila models of myosin-based Freeman-Sheldon syndrome. Mol Biol Cell. 2019 Jan 1;30(1):30-41. PubMed PMID: 30379605; PubMed Central PMCID: PMC6337914.

Abstract: "Using Drosophila melanogaster, we created the first animal models for myosin-based Freeman-Sheldon syndrome (FSS), a dominant form of distal arthrogryposis defined by congenital facial and distal skeletal muscle contractures. Electron microscopy of homozygous mutant indirect flight muscles showed normal (Y583S) or altered (T178I, R672C) myofibril assembly followed by progressive disruption of the myofilament lattice. In contrast, all alleles permitted normal myofibril assembly in the heterozygous state but caused myofibrillar disruption during aging. The severity of myofibril defects in heterozygotes correlated with the level of flight impairment. Thus our Drosophila models mimic the human condition in that FSS mutations are dominant and display varied degrees of phenotypic severity. Molecular modeling indicates that the mutations disrupt communication between the nucleotide-binding site of myosin and its lever arm that drives force production. Each mutant myosin showed reduced in vitro actin sliding velocity, with the two more severe alleles significantly decreasing the catalytic efficiency of actin-activated ATP hydrolysis. The observed reductions in actin motility and catalytic efficiency may serve as the mechanistic basis of the progressive myofibrillar disarray observed in the Drosophila models as well as the prolonged contractile activity responsible for skeletal muscle contractures in FSS patients."

Learn about Freeman-Sheldon syndrome online at the US NIH Genetic and Rare Diseases Information Center (GARD).

Review highlights role of zebrafish and Drosophila studies in understanding muscular dystrophies

Plantié E, Migocka-Patrzałek M, Daczewska M, Jagla K. Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish. Molecules. 2015 Apr 9;20(4):6237-53. PMID: 25859781.

From the abstract: "Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. ... To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs."

Review highlights fly research contributions to understanding muscular dystrophies

Plantié E, Migocka-Patrzałek M, Daczewska M, Jagla K. Model Organisms in the Fight against Muscular Dystrophy: Lessons from Drosophila and Zebrafish. Molecules. 2015 Apr 9;20(4):6237-6253. PMID: 25859781.

Table 1 from Plantie et al. Click to view the Open Access review.

From the abstract: "Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. ... Structurally, physiologically and biochemically, MDs affect different types of muscles and cause individual symptoms such that genetic and molecular pathways underlying their pathogenesis thus remain poorly understood. To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs."

New fly model of MEGF-associated congenital muscle disease

Draper I, Mahoney LJ, Mitsuhashi S, Pacak CA, Salomon RN, Kang PB. Silencing of Drpr Leads to Muscle and Brain Degeneration in Adult Drosophila. Am J Pathol. 2014 Aug 8. pii: S0002-9440(14)00374-5. PMID: 25111228.

From the abstract: "Mutations in the gene encoding the single transmembrane receptor multiple epidermal growth factor-like domain (MEGF) 10 cause an autosomal recessive congenital muscle disease in humans. ... Drpr is the sole Drosophila homolog of the human genes MEGF10, MEGF11, and MEGF12 (JEDI, PEAR). ... Our analysis of drpr mutant flies revealed muscle degeneration with fiber size variability and vacuolization, as well as reduced motor performance, features that have been observed in human MEGF10 myopathy. ... the absence of functional redundancy for Drpr in Drosophila may help elucidate whether paralogs of MEGF10 in humans (eg, MEGF11) contribute to maintaining wild-type function in the human brain."