Department of Regenerative Medicine and Cell Biology
Corey H. Mjaatvedt, Ph.D.
BS Microbiology Weber State College 1976
| Research Interest:
My interest is in understanding the functional role of the Extracellular Matrix (ECM) during development, injury and repair of the Heart, Inner Ear and Eye structures.Our lab has predominately focused on a complex ECM molecule called Versican (Vcan) and its role in heart development. More recently, however, through active collaborations with other labs, we are determining the important role Vcan plays in adult heart disease, hearing loss and vitreoretinal degenerative disorders.
Versican and Heart Developmental Biology:
My specific interest in versican’s (Vcan) role in the cardiovascular system began while at John’s Hopkins Medical Institute with an interesting transgene insertional mutant mouse that has a disrupted Vcan gene. This mouse we called heart defect (hdf) is a homozygous embryonic lethal. However, because the hdf transgene contains a lacZ reporter, partial expression of the Vcan gene can be tracked during heart embryogenesis within heterozygous mice (Fig 1). We found the heart Vcan -lacZ expression is highly and specifically expressed in the eye, limb bud, whisker follicles and the inner ear (Fig 2). For the last several years we have focused on different aspects of the role of Vcan in congenital heart disease with funds from a Grant-in-Aid from the American Heart Association and grants from the National Institute of Health NHLBHL66231-13.
Fig 1 Vcan expression (hdf lacZ) within E10.5pc heart.
Fig 2 hdf lacZ fusion protein shows Vcan’s expression is in the heart, limbs, eye, whisker follicles and inner ear.
Role for Vcan in the Adult Heart after Cardiac Injury:
In an ongoing collaboration with Dr. Claude Le Saux, an expert collagen deposition and fibrotic disease at the Buck Institute in San Francisco and University of Texas Health Science Center in San Antonio (UTHSCSA), we have identified changes in collagen and other ECM proteins in the Vcan mutant models after coronary ligation injury.
Fig 3 Vcan mutant after coronary ligation injury.
Role for Vcan in the Cochlea during Aging and after Injury:
In collaboration with Dr. Hainan Lang (Pathology; MUSC), and with funding from the National Institute of Health, we are pursuing the function of Vcan in the aging cochlea and after injury induced hearing loss (Fig 4). Without functional Vcan, mice fail to recover from noise induced hearing loss. As the “battery” of the cochlea, the lateral wall is critical for providing the high potassium, low sodium environment of the scala media for the normal function of hair cells. Dysfunction of any cell type in the cochlear lateral wall, including marginal, intermediate, and basal cells in stria vascularis, and fibrocytes or root cells in spiral ligament, will disrupt potassium cycling and effect the hearing function.
Fig 4 Vcan (green) inner ear.
Proposed K+ recycling and homeostasis in the mammalian inner ear. (Adapted from Steel 1999).
Vcan mutations cause Vitreoretinal Degenerative Disorders in humans:
In collaboration with Dr. Dieter R. Zimmermann (Zurich) the underlying mechanism through which single point Vcan mutations result in this degenerative disorder is being explored using mouse models of Vcan depletion Fig 5.
Fig 5 H&E image of the hdf
Extramural Grants/Award Amount:
10/01/2013-9/30/2018 NIDCD P50: Clinical Research Center. Experimental and Clinical Studies of Presbyacusis. Project 4: Human cochlear stem cells and the aging inner ear (Lang, PI; Mjaatvedt, Co-I). Purpose: To study adult stem cell dependency on the cochlear extracellular matrix (ECM) microenvironment in age-related hearing loss.
Previous Postdocs in the lab:
2001-2004 Russell A. Norris, Ph.D., Regenerative Medicine
2000- 2007 Christine B. Kern, Ph.D., Regenerative Medicine
2012-2013 Tara A, Burns, Ph.D., Regenerative Medicine
Medical Student Mentoring:
2000 Frank Ingram, 1st Medical Student Research Summer Award
Undergraduate Student Mentoring:
2006 April Lewis, Summer Student Research Award, Summer Undergraduate Research Program, MUSC
Sanon VP, Sawaki D, Mjaatvedt CH, Jourdan-Le Saux C: Myocardial tissue caveolae. Compr Physiol 2015, 5(2):871-886.
Shivshankar P, Halade GV, Calhoun C, Escobar GP, Mehr AJ, Jimenez F, Martinez C, Bhatnagar H, Mjaatvedt CH, Lindsey MLJourdan-Le Saux C: 2014. Caveolin-1 deletion exacerbates cardiac interstitial fibrosis by promoting M2 macrophage activation in mice after myocardial infarction. J Mol Cell Cardiol 2014, 76:84-93.
Burns T, Dours-Zimmermann MT, Zimmermann DR, Krug EL, Comete-Walter S, Reyes L, Davis MA, Schey KL, Schwacke JH, Kern C, Mjaatvedt, C H: 2014. Imbalanced expression of Vcan mRNA splice form proteins alters heart morphology and cellular protein profiles. PLoS One 9(2), 2014. PMID: 24586547
Mjaatvedt, C Mt Dours-Zimmermann, Dr Zimmerman, S Comete-Walter, K Schey, L Reyes, Schwacke, JH, Edward L Krug. 2013. Heart proteome ITRAQ analysis of mice with selective loss of Vcan exon 7 containing splice variants (dataset publication) https://www.researchgate.net/publication/234108313
Hudsen K, Andrews K, Early J, Mjaatvedt C, Capehart A. 2010. Versican G1 domain and V3 isoform overexpression results in increased chrondrogenesis in the developing chick limb in ovo. Anatomical Record 293:1669-1678.
Cooley MA, Kern CB, Fresco VM, Wessels A, Thompson RP, McQuinn T, Waleed TO, Mjaatvedt CH, Drake C, Argraves WS. 2008. Fibulin-1 is required for morphogenesis of neural crest-derived structures. Devel. Biol. 319:336-45
Williams# AD, Mjaatvedt CH, Moore CS. 2008. Characterization of the cardiac phenotype in neonatal Ts65Dn mice. Dev Dyn 237:426-435.
Wirrig# EE, Snarr# BS, Chintalapudi MR, O'Neal J L, Phelps AL, Barth JL, Fresco VM, Kern CB, Mjaatvedt CH, Toole BP, Hoffman S, Trusk TC, Argraves WS, Wessels A. 2007. Cartilage link protein 1 (Crtl1), an extracellular matrix component playing an important role in heart development. Dev Biol 310:291-303.
CB Kern, RA Norris, RP Thompson, L Reyes, S Hoffman, WS Argraves, RR Markwald, CH Mjaatvedt (2006)Versican proteolysis facilitates myocardial regression during outflow tract development. Devl. Dyn. 236:671-683.
Norris, R. A., Damon, B. J., Mironov, V., Kasyanov, V., Ramamurthi, A., Moreno-Rodriguez, R., Trusk, T., Potts, J. D., Goodwin, R. L., Davis, J., Hoffman, S., Wen, X., Sugi, Y., Kern, C. B., Mjaatvedt, C. H., Turner, D. K., Oka, T., Molkentin, J. D., Forgacs, G., and Markwald, R. R. (2006). Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues. Journal of Cellular Biochemistry 101:695-711.
JT Butcher, RA Norris, S Hoffman, CH Mjaatvedt, RR Markwald. (2006) Periostin promotes atrioventricular mesenchyme matrix invasion and remodeling mediated by integrin signaling through Rho/PI 3-kinase. Dev Biol. 302:256-266.
Hardy KM, Mjaatvedt CH, Antin PB. (2006). Hot hearts in the Sonoran desert: The 11th Weinstein cardiovascular development conference in Tucson. Dev Dyn 235:170-175.
Moreno-Rodriguez RA, Krug EL, Reyes L, Villavicencio L, Mjaatvedt CH, Markwald RR. (2006) Bidirectional fusion of the heart-forming fields in the developing chick embryo. Dev Dyn 235:191-202.
Mjaatvedt, C. H., Kern, C. B., Norris, R. A., Fairey, S., and Cave, C. L. (2005). The Normal Distribution Of Melanocytes In The Mouse Heart. Anat Rec A Discov Mol Cell Evol Biol 285:748-757.
Norris, R. A., Kern, C. B., Wessels, A., Wirrig, A. E., Markwald, R. R., and Mjaatvedt, C. H. (2005). Detection of Big-H3, a TGFB induced gene, during cardiac development and its complementary pattern with periostin. Anatomy & Embryology 210:13-23.
Kern, C. B., Hoffman, S., Moreno, R., Damon, B. J., Norris, R. A., Krug, E. L., Markwald, R. R., and Mjaatvedt, C. H. (2005). Immunolocalization of chick periostin protein in the developing heart. Anat Rec A Discov Mol Cell Evol Biol 284A, 415-423.
Snow, H. E., Riccio, L. M., Mjaatvedt, C. H., Hoffman, S., and Capehart, A. A. (2005). Versican expression during skeletal/joint morphogenesis and patterning of muscle and nerve in the embryonic mouse limb. Anat Rec A Discov Mol Cell Evol Biol 282, 95-105.
Williams DR, Jr., Presar AR, Richmond AT, Mjaatvedt CH, Hoffman S, Capehart AA. 2005. Limb chondrogenesis is compromised in the versican deficient hdf mouse. Biochem Biophys Res Commun 334:960-966
Brewer AC, Alexandrovich A, Mjaatvedt CH, Shah AM, Patient RK, Pizzey JA. 2005. GATA factors lie upstream of Nkx 2.5 in the transcriptional regulatory cascade that effects cardiogenesis. Stem Cells Dev 14:425-439.
Books And Other Monographs:
Markwald RR, Krug EL, Moreno R, Mjaatvedt CH, Ogawa M, Drake C, Visconti R, Kruzynska-Frejtag A, Conway SJ. 2003. Valvulogenesis: Role of Periostin in cushion Tissue Differentiation. In: Clark EB, Nkazawa M, Takao A, editors. Etiology and Morphogenesis of Congential Cardiovascular Disease in the Post-Genomic Era. Futura Publishing Company.
Mjaatvedt, C.H., Yamamura, H., Ramsdell, A.#, Turner, D. and Markwald, R.R. 1999. Mechanisms of segmentation and remodeling of the tubular heart: endocardial cushion fate and cardiac looping. In “Heart Development” eds. Richard P. Harvey and Nadia Rosenthal, Academic Press.
Markwald, R.R, Yamamura, H.+, De la Cruz, M.V., Litchenberg, W#. Gourdie, R., Thompson, R., Conway, S and C.H. Mjaatvedt. 1998. Segmental heart development of the hdf /versican gene In "Developmental Mechanisms of Heart Disease." EB Clark, RR Markwald, and A. Takao (eds.) Armonk, NY: Futura Publishing Company, Inc.
Lawler, A.M., C.H. Mjaatvedt, and J.D. Gearhart. 1993. Differential gene expression during early mammalian embryogenesis: Subtractive hybridization studies. In Methods in Molecular Biology Kenneth W. Adolph, ed., Academic Press, NY Vol. 1, pp. 51-67.
Markwald, R. R., E.L. Krug, C.H. Mjaatvedt, and A.R. Sinning. 1990. Endothelial formation of mesenchyme: induction by an extracellular glycoprotein complex. In Molecular Biology of the Cardiovascular system. Robert Roberts and Michael D. Schneider, eds. New York.
Yazhi Xing1, Kenyaria Noble1, Xin Liu1, Jianning Zhang1, Clarisse Panganiban1, LaShardai Conaway1, Richard Schmiedt2, Jeremy Barth3, Corey Mjaatvedt3, Hainan Lang1 2015. Extracellular Matrix Versican is Critical for the Maintenance of Mouse Auditory Sensitivity after Cochlear Injury. Association for Research in Otolaryngology, Feb. 21-25, 2015; Baltimore, MD
Mjaatvedt CH, Burns T, Escobar GP, Ansarizadeh Y, Le Saux CJ: Adverse cardiac remodeling mediated by the altered expression of versican. In: Experimental Biology: April 26-30, 2014; San Diego, CA. 2014.
Jourdan Le Saux, Claude1, Davis, Monica A2 and Krug, Edward L2, Mjaatvedt, Corey H Imbalance of Vcan Protein Expression Alters Collagen Deposition: Consequence for Heart Development. American Society for Matrix Biology and Society for Glycobiology Nov. 11-14 San Diego. 2013.
Mjaatvedt, Corey H2, Le Saux, Claude Jourdan1, Schwacke, John H2, Davis, Monica A2 and Krug, Edward L. Selective loss of Vcan Proteins Causes Heart Defects and Alters Collagen Deposition. 2Weinstein Cardiovascular Conference, May 5-9, 2012 Chicago, IL.
Mjaatvedt, CH2, Le Saux, CJ1, Schwacke, JH2 Davis, MA2 and Krug, EL2Selective loss of Vcan Proteins Causes Heart Defects and Related Changes in Collagen Deposition. Keystone Symposia “Cardiovascular Development and Regeneration” January 22-27, 2012 Taos, NM