Professor of Human Genetics and Adjunct Professor of Nutrition and Integrative Physiology
Musculoskeletal Development, Regeneration
How does muscle develop, regenerate, maintain, age, and evolve? These are the questions that drive our research. We focus on muscle stem cells because they are the source of all muscle. We focus on the muscle connective tissue because it provides the niche for muscle stem cells and is critical for muscle form and function. We study how interactions between muscle stem cells and the connective tissue orchestrate development of limb muscles and the diaphragm, regulate muscle regeneration and aging, are the source of birth defects and fibrosis, and shape evolution of the musculoskeletal system.
Muscle Stem Cells in Development, Regeneration, and Homeostasis
Muscle development, growth, and regeneration take place throughout vertebrate life. Muscle stem cells are critical for all of these processes. Our research has concentrated on the developmental origin of muscle stem cells, their function, and the extrinsic signals that regulate them. We have found that all muscle stem cells in the limb arise in the embryo from the somites, but there are related, although distinct populations of stem cells in the embryo, fetus, and adult (Kardon et al. 2002, Schienda et al. 2006, Hutcheson et al. 2009, Murphy et al. 2011). We also have established that muscle stem cells are critical for muscle development (Hutcheson et al. 2009) and satellite cells (the adult muscle stem cells) are necessary and sufficient for muscle regeneration (Murphy et al. 2011). Satellite cells also contribute to muscle homeostasis, but their requirement is still not clear (Keefe et al. 2015). Our current research concentrates on the molecular mechanisms and cellular interactions regulating satellite cells and regeneration.
Muscle Connective Tissue Regulation of Muscle and Fibrosis
Muscle connective tissue ensheathes muscles and maintains muscle architecture and transmits muscle contractile force to adjoining tendon and bone. In addition, the connective tissue is an important component of the niche regulating muscle stem cells. However, connective tissue must be precisely regulated as connective tissue fibrosis, which is a feature of chronic injury, aging, and disease, can seriously impair muscle strength and elasticity. We have found that the connective tissue regulates development of the diaphragm and limb muscles (Kardon et al. 2003; Mathew et al. 2011, Merrell et al. 2015) and expansion of satellite cells during muscle regeneration (Murphy et al. 2011). We are working to understand the molecular nature of this regulation. In addition, how the fibroblasts regulate fibrosis is an active area of our research.
Diaphragm: Development, CDH, and Evolution
The diaphragm is an essential mammalian skeletal muscle essential. It is vital for respiration and serves as a barrier between the abdomen the thorax (see our review Merrell et al. 2013 and Kardon et al. 2017) . Unfortunately, defects in development of the diaphragm are common in humans and lead to Congenital Diaphragmatic Hernias (CDH). We study the genetic, molecular, and cellular mechanisms regulating development of the diaphragm and CDH. Our research uses mouse genetics, ex vivo two photon imaging of the developing diaphragm, cell culture, and human genetics data. We have found that the connective tissue critically regulates development of the diaphragm and mutations in this tissue are a source of CDH (Merrell et al. 2015). Currently we are trying to understand the molecular nature of the connective tissue signaling to muscle. We also study evolution of the diaphragm - as the diaphragm is a unique and defining character of all mammals.
- Bogenschutz EL, Fox ZD, Farrell A, Wynn J, Moore B, Yu L, Aspelund G, Marth G, Yandell M. Shen Y, Chung WK, and Kardon G. 2020. Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias. HGG Advances 1(1)
- Bogenschutz EL, Sefton EM, Kardon G. 2020. Cell culture system to assay candidate genes and molecular pathways implicated in congenital diaphragmatic hernias. Developmental Biology 467(1-2):30-38.
- Sefton EM, Gallardo M, Kardon G. 2018. Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle. Developmental Biology 440(2):64-73
- Colasanto MP, S Eyal, P Mohassel, M Bamshad, C Bonnemman, E Zelzer, AM Moon, Kardon G. 2016. Development of a subset of forelimb muscles and their attachments sites requires the ulnar-mammary syndrome gene Tbx3. Disease Models and Mechanisms
- Keefe AC, Lawson JA, Flygare SD, Fox ZD, Colasanto MP, Mathew SJ, Yandell M, Kardon G. 2015. Muscle stem cells contribute to myofibres in sedentary adult mice. Nature Communications (6): 1-11.
- Merrell AJ, Ellis BJ, Fox ZD, Lawson JA, Weiss JA, Kardon G. 2015. Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. Nature Genetics 47(5): 496-505.
- Merrell AJ, Ellis BJ, Fox ZD, Lawson JA, Weiss JA, Kardon G. 2015. Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. Nature Genetics 47(5): 496-504.
- Keefe AC, Lawson JA, Flygare SD, Fox ZD, Colasanto MP, Mathew SJ, Yandell M, Kardon G. 2015. Muscle stem cells contribute to myofibres in sedentary adult mice. Nature Communications 6: 7087.
- Rohatgi A, Corbo JC, Monte K, Higgs S, Vanlandingham DL, Kardon G, Lenschow DJ. 2014. Infection of myofibers contributes to increased pathogenicity during infection with an epidemic strain of Chikungunya virus. Journal of Virology 88(5): 2414-2425.
- Murphy MM, Keefe AC, Lawson JA, Flygare SD, Yandell M, Kardon G. 2014. Transiently active Wnt/β-catenin signaling is not required but must be silenced for stem cell function during muscle regeneration. Stem Cell Reports 3(3): 475-88.
- Merrell AJ and Kardon G. 2013. Development of the diaphragm – a skeletal muscle essential for mammalian respiration. FEBS Journal 270(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.
- 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.
- Murphy MM, Lawson JA, Mathew SJ, Hutcheson DA, Kardon G. 2011. Satellite cells, connective tissue fibroblasts, and their interactions are crucial for muscle regeneration. Development 138(17): 3625-3637.
- Mathew SJ, Hansen JM, Merrell AJ, Murphy MM, Lawson JA, Hutcheson DA, Hansen MS, Angus-Hill M, Kardon G. Connective tissue fibroblasts and Tcf4 regulate myogenesis. Development 138: 371-384.
- Hutcheson DA, Zhao J, Merrell AJ, Haldar M, Kardon G. 2009. Embryonic and fetal limb myogenic cells are derived from developmentally distinct progenitors and have different requirements for b-catenin. Genes and Development 23(8): 997-1013.
- Schienda J, Engleka K, Sun KS, Hansen MS, Epstein J, Tabin CJ, Kunkel LM, Kardon G. 2006. Somitic origin of limb muscle satellite and side population cells. PNAS 103(4): 945-950.
- Kardon G, Harfe BD, Tabin CJ. 2003. A Tcf4-positive mesodermal population provides a prepattern for vertebrate limb muscle patterning. Developmental Cell 5: 937-944.
- Kardon G, Campbell JK, Tabin CJ. 2002. Local extrinsic signals determine muscle and endothelial cell fate and patterning in the vertebrate limb. Developmental Cell 3: 533-546.