The vertebrate musculoskeletal system is essential for the support and movement of the body. To enable a wide variety of movements, the musculoskeleton is complex, consisting of more than 200 muscles attached via muscle connective tissue and tendons to bones. The broad aim of our laboratory is to understand the molecular mechanisms and tissue interactions necessary to pattern and assemble the musculoskeletal system during development and also their role in regeneration and disease. We focus on the muscle connective tissue because it is critical for the form and function of the musculoskeleton, muscle development and regeneration, and defects in muscle and its connective tissue result in devastating congenital muscular dystrophies. Using the chick and mouse model systems, we are using gain and loss-of-function experiments to test the role of muscle cells, connective tissue fibroblasts, and various signaling pathways in mediating the interactions between muscle and connective tissue.
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The proper development of the musculoskeleton requires the coordinated morphogenesis of muscle, muscle connective tissue, tendon, and skeleton. Our initial research has focused on the development of the vertebrate limb musculoskeleton. With its accessibility to embryological and molecular manipulations, the vertebrate limb has been a classic system for studying morphogenesis. During development, the limb muscle derives from migratory precursors originating from the somites, while the muscle connective tissue, tendons, and skeleton develop from the lateral plate mesodermal cells of the emerging limb bud. As the muscle precursors migrate into the limb they must differentiate into myofibers, become correctly patterned into distinct anatomical muscles, and be assembled with muscle connective tissue, tendons, and skeletal elements into a functional musculoskeletal system. Our recent research has demonstrated that limb embryonic and fetal muscle cells develop from distinct, but related progenitors and have different cell-autonomous requirements for b-catenin. In addition we have found that both muscle cell fate and patterning is determined by local extrinsic signals within the developing limb. We have determined that connective tissue fibroblasts, which express the transcription factor Tcf4 (a downstream effector of canonical Wnt/b-catenin signaling), are critical for proper muscle development. We are currently examining the role of Tcf4+ fibroblasts in regulating muscle cell fate and patterning and production of muscle connective tissue.
Vertebrate muscle has a remarkable capacity for regeneration. During the regenerative process, muscle and its surrounding connective tissue need to be repaired and structurally and functionally integrated with tendons and bones to restore musculoskeletal function. The regeneration of myofibers appears to be largely mediated by resident myogenic stem cells called satellite cells. During regeneration, satellite cells become activated, proliferate, and differentiate to repair damaged myofibers. Another important component of muscle regeneration is the transient increase of the surrounding muscle connective tissue, termed fibrosis. This fibrosis maintains the structure of the damaged muscle, but must be carefully regulated since excessive fibrosis can inhibit muscle regeneration. Our previous research has demonstrated that the great majority of satellite cells derive in development from the somites. We are currently testing the role of satellite cells and connective tissue fibroblasts in restoration of muscle and connective tissue structure and function during regeneration.
Duchenne Muscular Dystrophy (DMD) is a fatal disease affecting 1 in 3300 boys. It results from mutations in the dystrophin gene, whose protein is essential for muscle structure and function. DMD is characterized by both pathological muscle degeneration and regeneration and extensive fibrosis. Therefore interactions between connective tissue fibroblasts, satellite cells, and fibrosis are likely critical for DMD pathology. We are investigating how interactions between muscle and connective tissue contribute to the pathology of DMD.
References to Publications:
Murphy MM, Keefe AC, Lawson JA, Flygare SD, Yandell, M, Kardon G. 2014. Transiently active Wnt/b-catenin signaling is not required but must be silenced for stem cell function during muscle regeneration. Stem Cell Reports 3: 1-14.
Lours-Calet C, Alvares LE, El-Hanfy AS, Gandesha S, Walters EH, Sobreira DR, Wotton KR, Jorge EC, Lawson JA, Kelsey Lewis A, Tada M, Sharpe C, Kardon G, Dietrich S. 2014. Evolutionary conserved morphogenetic movements at the vertebrate head-trunk interface coordinate the transport and assembly of hypopharyngeal structures. Dev. Biol. 390(2); 231-246.
Rohatgi A, Corbo JC, Monte K, Higgs S, Vanlandingham DL, Kardon G, Lenschow DJ. Infection of myofibers contributes to increased pathogenicity during infection with an epidemic strain of chikungunya virus. J Virology 88(5): 2414-2425.
Merrell AJ and Kardon G. 2013. Development of the diaphragm – a skeletal muscle essential for mammalian respiration. FEBS Journal 280(17): 4026-4035.
Hu JK-H, McGlinn E, Harfe BD, Kardon G, Tabin CJ. 2012. Autonomous and non-autonomous roles of hedgehog signaling in regulating limb muscle formation. Genes and Development 26:2088-2102. PMC3444734.
Wan Y, Lewis AK, Colasanto M, van Langeveld M, Kardon G, Hansen C. 2012. A practical workflow for making anatomical atlases in biological research. IEEE Computer Graphics and Applications’ Special Issue – Biomedical Applications: From Data Capture to Modeling 99: 70-80. PMC111826294.
Wan, Y., A. K. Lewis, M. Colasanto, M. van Langeveld, G. Kardon, C. Hansen. in press. A practical workflow for making anatomical atlases for biological research. IEEE Computer Graphics and Applications’ Special Issue – Biomedical Applications: From Data Capture to Modeling.
Murphy, M. M., J. A. Lawson, S. J. Mathew, D. A. Hutcheson, and G. Kardon. 2011. Satellite cells, connective tissue fibroblasts and their interactions are critical for muscle regeneration. Development 138:3625-3637 (Featured article; Recommended by Faculty of 1000)
Mathew, S.J., Hansen, J. M. , Merrell, A. J., Murphy, M. M., Lawson, J. A., Hutcheson, D. A., Hansen, M. S., Angus-Hill, M., G. Kardon. 2011. Connective tissue fibroblasts and Tcf4 regulate myogenesis. Development 138:371-384. (Cover Illustration; Featured article; Recommended by Faculty of 1000)
Murphy, M. M. and G. Kardon. 2011. Origin of vertebrate limb muscle: the role of progenitors and myoblasts. Current Topics in Developmental Biology 96: 1-32.
Kardon, G. 2011. Development of the musculoskeletal system: meeting the neighbors. Development 138:2855-2859.
Hutcheson, D. A., Zhao, J., Merrell, A., Haldar, M., G. Kardon. 2009. Embryonic and fetal limb myogenic cells are derived from developmentally distinct progenitors and have different requirements for -catenin. Genes and Development 23(8): 997-1013. (Cover Illustration; Perspective by Messina and Cossu)
Hutcheson, D. A. and G. Kardon. 2009. Genetic manipulations reveal dynamic cell and gene functions; Cre-ating a new view of myogenesis. Cell Cycle 8(22): 1-4.
Schienda, J,, K. Engleka, , S. Jun, M. S. Hansen, J. Epstein, C. J. Tabin, L. M. Kunkel, G. Kardon. 2006. Somitic origin of limb muscle satellite and side population cells. PNAS 103(4): 945-950.
Kardon, G., T. A. Heanue, C. J. Tabin. 2004. The Pax/Six/Eya/Dach network in development and evolution. In Modularity in Development and Evolution, eds. G. Schlosser and G. Wagner, Chicago University Press.
Kardon, G., B. D. Harfe, C. J. Tabin. 2003. A Tcf4-positive mesodermal population provides a prepattern for vertebrate limb muscle patterning. Developmental Cell 5: 937-944.
Kardon, G., J. K. Campbell, C. J. Tabin. 2002. Local extrinsic signals determine muscle and endothelial cell fate and patterning in the vertebrate limb. Developmental Cell 3: 533-546.
Kardon, G., T. A. Heanue, C. J. Tabin. 2002. Pax3 and Dach2 positive regulation in the developing somite. Developmental Dynamics 224(3): 350-355.
Kardon, G. 1998. Muscle and tendon morphogenesis in the avian hind limb. Development 125(20): 4019-4032. (Cover Illustration)
Kardon, G. 1998. Evidence from the fossil record of an antipredatory exaptation: conchiolin layers in corbulid bivalves. Evolution 52(1): 68-79.
Gabrielle Kardon, Ph.D.
Department of Human Genetics
University of Utah
15 N 2030 E RM 6110
Salt Lake City, Utah 84112-5330
801-585-6184 – office
801-585-7365 – lab