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Research Interests   Molecular Basis of Muscular Dystrophy; Role of Actin in Cell Polarity

My Laboratory primarily studies the structure and cellular function of the dystrophin-glycoprotein complex, which spans the muscle cell plasma membrane (or sarcolemma) and links the cortical actin cytoskeleton with the extracellular matrix. Greater understanding of the physiologic role of the dystrophin-glycoprotein complex is necessary to understand how its absense or abnormality leads to several muscular dystrophies and some forms of human dilated cardiomyopathy. The lab has defined the complete actin-binding region of 400 kDa dystrophin and shown that its homologue utrophin binds actin filaments through a distinct molecular mechanism. Novel methods to visualize the sarcolemmal cytoskeleton without interference from internal structures provided the first evidence that dystrophin functions in vivo to mechanically stabilize γ-actin filaments in costameres. Studies of dystrophin-deficient mice and new animal models generated by the lab have provided insight into the funtion of costameres in striated muscle and suggest novel links between dystrophin deficiency and alterations cell signaling, or gene expression manifest by dystrophic muscle.

My lab's unique capability to express biochemical amounts of full-length dystrophin and utrophin has made possible new studies to i)characterize the effects of dystrophy-causing point mutations on dystrophin structure/function, ii) to identify novel associated proteins and iii) to develop new protein-based therapies for dystrophinopathies. In a completely new line of investigation, my group is working to determine the potentially unique roles of non-muscle actin isoforms in the establishment/maintenance of cell polarity in a variety of tissue. The β- and γ-isoforms of actin distribute to distinct locations within a variety of polarized cell types, including neurons, epithelial cells, and hair cells of the inner ear yet β- and γ-isoforms differ from each other by only 4 amino acids. Using new isoform-specific reagents and conditional knock-out mouse lines developed during the course of our muscular dystrophy studies, the lab is now poised to identify non-overlapping functions of these two highly conserved and widely expressed proteins.

Prins, K.W., Humston, J.M., Mehta, A., Tate, V., Ralston, E. and Ervasti, J.M.  (2009) Dystrophin is a microtubule-associated protein J. Cell Biol. 186:363-369.

Belyantseva, I.A., Perrin, B.J., Sonnemann, K.J., Zhu, M., Stepanyan, R., McGee, J., Frolenkov, G.A., Walsh, E.J., Friderici, K.H., Friedman, T.B. and Ervasti, J.M. (2009) g-Actin is required for cytoskeletal maintenance but not development. Proc. National Acad. Sci. USA 106:9703-9708.

Sonnemann, K.J., Heun-Johnson, H., Turner A.J., Baltgalvis, K., Lowe D.A. and Ervasti, J.M. (2009) Functional substitution by TAT-utrophin in dystrophin deficient mice. PLoS Med. 6:e1000083.

Prochniewicz, E., Henderson, D.M., Ervasti, J.M. and Thomas, D.D. (2009) Dystrophin and utrophin have distinct effects on the structural dynamics of actin Proc. National Acad. Sci. USA 106:7822-7827.

Jaeger, M.A., Sonnemann, K.J., Fitzsimons, D., Prins, K.W. and Ervasti, J.M. (2009) Context dependent functional substitution of a-skeletal actin by g‑cytoplasmic actin FASEB J. 23:2205-2214.

Bunnell, T.M., Jaeger M.A., Fitzsimons, D.P., Prins, K.W. and Ervasti, J.M. (2008) Destabilization of the dystrophin-glycoprotein complex without functional deficits in α‑dystrobrevin null muscle PLoS One 3:e2604.

Prins K.W., Lowe D.A. and Ervasti, J.M. (2008) Skeletal muscle-specific ablation of gcyto-actin does not exacerbate the mdx phenotype. PLoS One 3:e2419.

Ervasti, J.M. and Sonnemann, K.J. (2008) Biology of the Dystrophin-Glycoprotein Complex. In: International Review of Cytology; A Survey of Cell Biology (K.W. Jeon, ed.) Ch. 5, pp. 191-225, Elsevier, San Diego.

Ervasti, J.M. (2006) Dystrophin, its interactions with other proteins, and implications for muscular dystrophy. BBA Molec. Basis Dis. 1172:108-117.

Sonnemann, K.J., Fitzsimons, D.P., Patel, J.R., Liu, Y.W., Schneider, M.F., Moss, R.L. and Ervasti, J.M. (2006) Cytoplasmic γ-actin is not required for skeletal muscle development but its absence leads to a progressive myopathy. Dev. Cell 11:387-397.

Hanft, L.M., Rybakova, I.N., Patel, J.R., Rafael, J.A. and Ervasti, J.M. (2006) Cytoplasmic γ-actin contributes to a compensatory remodeling response in dystrophin-deficient muscle. Proc. National Acad. Sci. USA 103:5385-5390.

Rybakova, I.N., Humston, J.L., Sonnemann, K.J. and Ervasti, J.M. (2006) Dystrophin and utrophin bind actin filaments through distinct modes of contact. J. Biol. Chem. 281:9996-10001.

Rybakova, I.N. and Ervasti, J.M. (2005) Identification of spectrin-like repeats required for high affinity utrophin/actin interaction.J. Biol. Chem. 280:23018-23023.

Ervasti, J.M. (2003) Costameres: the Achilles' Heel of Herculean Muscle. J. Biol. Chem. 278:13591-13594.

Galkin, V.E., Oriova, A., Vanloock, M.S., Rybakova, I.N., Ervasti, J.M. and Egelman, E.H. (2002) The utrophin actin-binding domain binds F-actin in two differnt modes: implications for the spectrin superfamily of proteins. J. Cell Biol. 157:243-251.

Warner, L.E., Dello Russo, C., Crawford, R.W., Rybakova, I.N., Patel, J.R., Ervasti, J.M. and Chamberlain, J.S. (2002) Expression of Dp260 in muscle tethers the actin cytoskeleton to the dystrophin-glycoprotein complex and partially prevents dystrophy. Hum. Mol. Genet. 11:1095-1105.

Rybakova, I.N., Patel, J.R., Yurchenco, P.D., Davies, K.E. and Ervasti, J.M. (2002) Utrophin binds laterally along actin filaments and can couple costameric actin with sarcolemma when overexpressed in dystrophin-deficient muscle. Mol. Biol. Cell 13:1512-1521.

Rybakova, I.N., Patel, J.R. and Ervasti, J.M. (2002) The dystrophin complex forms a mechanically strong link between the sarcolemma and costameric actin. J. Cell Biol. 150:1209-1214.