Genetics of Wound Healing
We have established that adult MRL mice show unique regenerative responses. These include 1) the closure of through-and-through ear holes, 2) the re-growth of cartilage and hair follicles, and 3) the healing of heart tissue after a cryoinjury to the right ventricle without scarring, with the near full replacement of cardiomyocytes, and with return to normal heart function. We have also demonstrated that the ear hole closure phenotype is controlled by multiple genetic loci, behaves as a true quantitative trait, and is profoundly influenced by sex.
We will identify the genes that regulate healing in these mouse strains, using a combination of linkage mapping and gene expression profiling. The inbred MRL mouse strain derives from the LG mouse strain, which to date is the only other mouse strain shown to have this regenerative capacity. A panel of recombinant inbred (RI) lines and an Advanced Intercross Line (AIL) between LG/J (large) and SM/J (small) mice has been constructed. We are examining their ability to regenerate, to explore the full range of their healing phenotypes, and to map the regeneration genes in this MRL progenitor.
Dr. Ellen Heber-Katz, Wistar Institute
Dr. Libby Blankenhorn, Drexel University
Supported by NIGMS grant GM073226
Publications on the Topic
Rai, MF, EJ Schmidt, S Hashimoto, JM Cheverud, LJ Sandell. 2015. Genetic Loci that Regulate Ectopic Calcification in Response to Knee Trauma in LG/J by SM/J Advanced Intercross Mice. Journal of Orthopaedic Research (in press).
Cheverud, J. M., H. A. Lawson, K. Bouckaert, A. V. Kossenkov, L. C. Showe, L. Cort, E. P. Blankenhorn, K. Bedelbaeva, D. Gourevitch, Y. Zhang, and E. Heber-Katz. 2014. Fine-mapping quantitative trait loci affecting murine external ear tissue regeneration in the LG/J by SM/J advanced intercross line. Heredity 112: 508-518. doi: 10.1038/hdy.2013.133
Rai, M. F., E. J. Schmidt, A. McAlinden, J. M. Cheverud and L. J. Sandell. 2013. Molecular insight into the association between cartilage regeneration and ear wound healing in genetic mouse models: Targeting new genes in regeneration. G3: Genes, Genomes, Genetics, 3: 1881-1891.
Rai, M. F., L. J. Sandell, J. M. Cheverud, and R. H. Brophy. 2013. Relationship of age and body mass index to the expression of obesity and osteoarthritis related genes in human meniscus. International Journal of Obesity 37: 1238-1246.
Hashimoto, S., M.F. Rai, K. L. Janiszak, J. M. Cheverud and L. J. Sandell. 2012. Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM Recombinant Inbred mice. Osteoarthritis and Cartilage 20:562-571.
Rai, M. F., S. Hashimoto, E. E. Johnson, K. L. Janiszak, J. Fitzgerald, E. Heber-Katz, J. M. Cheverud, and L. J. Sandell. 2012. Heritability of articular cartilage regeneration and its association with ear-wound healing. Arthritis & Rheumatism 64: 2300-2310.
Cheverud, J. M., H. A. Lawson, R. Funk, J. Zhou, E. P. Blankenhorn, and E. Heber-Katz. 2012. Healing quantitative trait loci in a combined cross analysis using related mouse strain crosses. Heredity 108: 441-446.
Bedelbaeva, K., A. Snyder, D. Gourevitch, L. Clark, X.-M. Zhang, J. Leferovich, J. M. Cheverud, P. Lieberman, and E. Heber-Katz. 2010. Lack of p21 expression links cell cycle control and appendage regeneration in mice. Proceedings of the National Academy of Sciences, 107: 5845-5850.
Blankenhorn, E, G Bryan, A Kossenkov, L Clark X-M Zhang, C Chang, W Homg, LS Pletscher, J Cheverud, L Showe, and E Heber-Katz. 2009. Genetic loci that regulate healing and regeneration in LG/J and SM/J mice. Mammalian Genome 20: 720-733.
Rogers, J., M. Raveendran, G. L. Fawcett, A. S. Fox, S. E. Shelton, J. A. Oler, J. M. Cheverud, D. M. Muzny, R. A. Gibbs, R. J. Davidson, and N. H. Kalin. 2013. CRHR1 genotypes, neural circuits, and the diathesis for anxiety and depression. Molecular Psychiatry 18: 700-707.
Sussman, R. W., P. A. Garber and J. M. Cheverud. 2010. Reply to Lawler: Feeding competition, cooperation, and the causes of primate sociality. American Journal of Primatology 73: 91-95.
Thach, B. T., J. P. Kenney-Hunt, T. C. Simon, J. L. Stratman, S. B. Thach, K. A. Harris, S. Saunders and J. M. Cheverud. 2009. Sex-specific quantitative trait loci linked to autoresuscitation failure in SWR/J mice. Heredity 103: 469-475.