Our objective is to fully define the function of dystrophin in striated muscle to understand how its absence or abnormality leads to the pathologies observed in Duchenne and Becker muscular dystrophies. Our unique approach integrates biochemical and biophysical analyses of the very large dystrophin protein with in vivo assessments of its function in transgenic mouse models of muscular dystrophy.
Ph.D., University of Minnesota, 1989
Belanto, J.J., Mader, T., Eckhoff, M., Strandjord, D.M., Banks, G.B., Gardner, M.K., Lowe, D.A. and Ervasti J.M. (2014) Microtubule Binding Distinguishes Dystrophin from Utrophin. Proc Natl. Acad. Sci. USA 111:5723-5728. PMCID: PMC3992671
Perrin B.J., Strandjord, D.M., Narayanan, P., Henderson, D.M., Johnson, K.R. and Ervasti, J.M. (2013) β-Actin and fascin-2 cooperate to maintain stereocilia length. J. Neurosci. 33:8114. PMCID: PMC3718021
Lin, A.Y., Prochniewicz, E., Henderson, D.M., Li, B., Ervasti, J.M. and Thomas, D.D. (2012) Impacts of dystrophin and utrophin domains on actin structural dynamics: implications for therapeutic design. J. Mol. Biol. 420:87-98. PMCID: PMC3367031
Henderson, D.M., Lin, A.Y., Thomas, D.D. and Ervasti, J.M. (2012) The Carboxy-Terminal Third of Dystrophin Enhances Actin Binding Activity. J. Mol. Biol. 416:414-424. PMCID: PMC3273627
Zhang, D.-S., Piazza, V., Perrin, B.J., Rzadzinska, A.K., Poczatek, J.C., Wang, M., Prosser, H.M., Ervasti, J.M., Corey, D.P. and Lechene, C.P. (2012) Multi-isotope imaging mass spectrometry reveals slow protein turnover in stereocilia of inner-ear hair cells. Nature 481:520–524. PMCID: PMC3267870
Baltgalvis, K.A., Jaeger, M.A., Fitzsimons, D.P., Thayer, S.A., Lowe, D.A. and Ervasti, J.M. (2011) Transgenic over-expression of Îł-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice. Skeletal Muscle 1:32. PMCID: PMC3214766
Henderson, D.M., Belanto, J.J., Li, B., Heun-Johnson, H. and Ervasti, J.M. (2011) Internal deletion compromises the stability of dystrophin Hum. Mol. Genet. 20:2955-2963. PMCID: PMC3131041
Bunnell, T.M., Burbach, B.J., Shimizu, Y. and Ervasti, J.M. (2011) β-actin specifically controls cell growth, migration and the G-actin pool. Mol. Biol. Cell 22:4047-4058. PMCID: PMC3204067
Prins, K.W., Call, J.A., Lowe, D.A and Ervasti, J.M. (2011) Quadriceps myopathy caused by skeletal muscle specific ablation of βcyto-actin. J. Cell Sci. 124:951-957. PMCID: PMC3048892
Henderson, D.M., Lee, A. and Ervasti, J.M. (2010) Disease-Causing Missense Mutations in Actin Binding Domain 1 of Dystrophin Induce Thermodynamic Instability and Protein Aggregation. Proc. National Acad. Sci. USA 107:9632-9637. PMCID: PMC2906886
Perrin, B.J., Sonnemann, K.J and Ervasti, J.M. (2010) β-actin and γ-actin are each dispensible for auditory hair cell development but required for stereocilia maintenance. PLoS Genetics 6:e1001158. PMCID: PMC2954897
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) Îł-Actin is required for cytoskeletal maintenance but not development. Proc. National Acad. Sci. USA 106:9703-9708. PMCID: PMC2701000
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. PMCID: PMC2728405
Bunnell, T.M. and Ervasti, J.M. (2010) Delayed embryonic development and impaired cell growth and survival in Actg1 null mice. Cytoskeleton 67:564-572.
Henderson, D.M., Lee, A. and Ervasti, J.M. (2010) Disease-Causing Missense Mutations in Actin Binding Domain 1 of Dystrophin Induce Thermodynamic Instability and Protein Aggregation. Proc. National Acad. Sci. USA 107:9632-9637.
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) ?-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. PDF
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 ?-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 a-dystrobrevin null muscle PLoS One 3:e2604.
Prins K.W., Lowe D.A. and Ervasti, J.M. (2008) Skeletal muscle-specific ablation of ?cyto-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. (2007) Dystrophin, its interactions with other proteins, and implications for muscular dystrophy. BBA Molec. Basis Dis. 1772:108-117 (Published online June 7, 2006 DOI 10.1016/j.bbadis.2006.05.010).
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 absence or abnormality leads to Duchenne muscular dystrophy and 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 ?-actin filaments in costameres. Studies of dystrophin-deficient mice and new animal models generated by the lab have provided insight into the function of costameres in striated muscle and suggest novel links between dystrophin deficiency and alterations in 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 tissues. The ?- and ?-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 ?- and ?-actin 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 working to identify non-overlapping functions of these two highly conserved and widely expressed proteins.
