University of Minnesota
University of Minnesota
College of Biological Sciences
http://www.cbs.umn.edu/

James M. Ervasti

Ph.D., University of Minnesota, 1989
Professor, BMBB
(612) 626-6517

Office: 7-104 MCB

Laboratory: 7-222 MCB
Lab Telephone: (612) 624-9294


Ervasti Lab Website

Research Description

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.  We have shown that dystrophin is a monomer that binds laterally along an actin filament through the concerted actions of two distinct and spatially separated actin binding sites and is necessary for strong mechanical coupling between the sarcolemma and costameric actin filaments.  We have also demonstrated that the dystrophin homologue utrophin can substitute for dystrophin in coupling costameric actin filaments to the sarcolemma when transgenically overexpressed in dystrophin-deficient skeletal muscle and binds actin filaments with similar affinity as dystrophin, but through distinct modes of contact.  Finally, we showed that dystrophin directly binds to microtubules and is required to organize the subsarcolemmal microtubule lattice of skeletal muscle.  Several of these advances were made possible by methods that we pioneered to express and purify biochemical amounts of full-length recombinant dystrophin and utrophin. Continuing to build on the project’s history of innovation, we have developed new cell and animal models that enable us to investigate the critical roles of roles of cytoplasmic non-muscle actin isoforms in skeletal muscle.  We are also investigating small molecule approaches to stabilize aberrant dystrophins expressed in some muscular dystrophy patients. Finally, we are also pursuing state-of-the-art in vivo rescue experiments and proteomic screens to further define the physiological role of microtubule lattice organization by dystrophin.



 

Recent Publications

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 γ-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) γ-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).