Associate Professor of Human Genetics
Co-Director MD-PhD Training Program
B.S. Yale University
Ph.D. Duke University
Gabrielle Kardon's Lab Page
Gabrielle Kardon's PubMed Literature Search
Molecular Biology Program
Musculoskeletal Development, Regeneration
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 muscle and its connective tissue because they are critical for the form and function of the musculoskeleton, and defects in muscle and its connective tissue result in devastating congenital muscular dystrophies. Using the mouse and chick model systems, we are testing the role of muscle cells, connective tissue fibroblasts, and various signaling pathways in mediating the interactions between muscle and connective tissue. This research will both increase our understanding of normal musculoskeletal development and regeneration and give us insights into the causes of human musculoskeletal diseases.
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 β-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/β-catenin signaling), are critical for proper muscle development. We are currently examining how Tcf4+ fibroblasts regulate 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 is 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. Using mouse genetics, we have demonstrated that satellite cells are the endogenous stem cell required for muscle regeneration and show that connective tissue fibroblasts are a vital component of the niche regulating satellite cell expansion during regeneration. Currently we are testing what molecular signals from fibroblasts regulate satellite cell kinetics.
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.
- 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.
- 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.