Abstract
MRL mice display unusual healing properties. When MRL ear pinnae are hole punched, the holes close completely without scarring, with regrowth of cartilage and reappearance of both hair follicles and sebaceous glands. Studies using (MRL/lpr × C57BL/6)F2 and backcross mice first showed that this phenomenon was genetically determined and that multiple loci contributed to this quantitative trait. The lpr mutation itself, however, was not one of them. In the present study we examined the genetic basis of healing in the Large (LG/J) mouse strain, a parent of the MRL mouse and a strain that shows the same healing phenotype. LG/J mice were crossed with Small (SM/J) mice and the F2 population was scored for healing and their genotypes determined at more than 200 polymorphic markers. As we previously observed for MRL and (MRL × B6)F2 mice, the wound-healing phenotype was sexually dimorphic, with female mice healing more quickly and more completely than male mice. We found quantitative trait loci (QTLs) on chromosomes (Chrs) 9, 10, 11, and 15. The heal QTLs on Chrs 11 and 15 were linked to differential healing primarily in male animals, whereas QTLs on Chrs 9 and 10 were not sexually dimorphic. A comparison of loci identified in previous crosses with those in the present report using LG/J × SM/J showed that loci on Chrs 9, 11, and 15 colocalized with those seen in previous MRL crosses, whereas the locus on Chr 10 was not seen before and is contributed by SM/J.
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References
Armstrong JR, Ferguson MW (1995) Ontogeny of the skin and the transition from scar-free to scarring phenotype during wound healing in the pouch young of a marsupial, Monodelphis domestica. Dev Biol 169:242–260
Blankenhorn EP, Troutman S, Clark LD, Zhang XM, Chen P et al (2003) Sexually dimorphic genes regulate healing and regeneration in MRL mice. Mamm Genome 14:250–260
Burgess-Herbert SL, Cox A, Tsaih SW, Paigen B (2008) Practical applications of the bioinformatics toolbox for narrowing quantitative trait loci. Genetics 180:2227–2235
Cheverud JM, Ehrich TH, Hrbek T, Kenney JP, Pletscher LS et al (2004) Quantitative trait loci for obesity- and diabetes-related traits and their dietary responses to high-fat feeding in LGXSM recombinant inbred mouse strains. Diabetes 53:3328–3336
Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138:963–971
Clark LD, Clark RK, Heber-Katz E (1998) A new murine model for mammalian wound repair and regeneration. Clin Immunol Immunopathol 88:35–45
Delerive P, Monte D, Dubois G, Trottein F, Fruchart-Najib J et al (2001) The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response. EMBO Rep 2:42–48
Ehrich TH, Kenney JP, Vaughn TT, Pletscher LS, Cheverud JM (2003) Diet, obesity, and hyperglycemia in LG/J and SM/J mice. Obes Res 11:1400–1410
Ehrich TH, Kenney-Hunt JP, Pletscher LS, Cheverud JM (2005) Genetic variation and correlation of dietary response in an advanced intercross mouse line produced from two divergent growth lines. Genet Res 85:211–222
Fitzgerald J, Rich C, Burkhardt D, Allen J, Herzka AS et al (2008) Evidence for articular cartilage regeneration in MRL/MpJ mice. Osteoarthritis Cartilage 16:1319–1326
Goodale H (1938) A study of the inheritance of body weight in the albino mouse by selection. J Hered 29:101–112
Goss RJ, Grimes LN (1975) Epidermal downgrowths in regenerating rabbit ear holes. J Morphol 146:533–542
Gourevitch D, Clark L, Chen P, Seitz A, Samulewicz SJ et al (2003) Matrix metalloproteinase activity correlates with blastema formation in the regenerating MRL mouse ear hole model. Dev Dyn 226:377–387
Guenther C, Pantalena-Filho L, Kingsley DM (2008) Shaping skeletal growth by modular regulatory elements in the Bmp5 gene. PLoS Genet 4:e1000308
Gunning P, O’Neill G, Hardeman E (2008) Tropomyosin-based regulation of the actin cytoskeleton in time and space. Physiol Rev 88:1–35
Heber-Katz E, Chen P, Clark L, Zhang XM, Troutman S et al (2004) Regeneration in MRL mice: further genetic loci controlling the ear hole closure trait using MRL and M. m. castaneus mice. Wound Repair Regen 12:384–392
Hopkinson-Woolley J, Hughes D, Gordon S, Martin P (1994) Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse. J Cell Sci 107(Pt 5):1159–1167
Hrbek T, de Brito RA, Wang B, Pletscher LS, Cheverud JM (2006) Genetic characterization of a new set of recombinant inbred lines (LGXSM) formed from the inter-cross of SM/J and LG/J inbred mouse strains. Mamm Genome 17:417–429
Huang JD, Brady ST, Richards BW, Stenolen D, Resau JH et al (1999) Direct interaction of microtubule- and actin-based transport motors. Nature 397:267–270
Kench JA, Russell DM, Fadok VA, Young SK, Worthen GS et al (1999) Aberrant wound healing and TGF-beta production in the autoimmune-prone MRL/+mouse. Clin Immunol 92:300–310
Kramer MG, Vaughn TT, Pletscher LS, King-Ellison K, Adams E et al (1998) Genetic variation in body weight gain and composition in the intercross of Large (LG/J) and Small (SM/J) inbred strains of mice. Genet Mol Biol 21:211–218
Krendel M, Osterweil EK, Mooseker MS (2007) Myosin 1E interacts with synaptojanin-1 and dynamin and is involved in endocytosis. FEBS Lett 581:644–650
Li XM, Gu WK, Masinde G, Hamilton-Ulland M, Xu SZ et al (2001) Genetic control of the rate of wound healing in mice. Heredity 86:668–674
MacArthur J (1944) Genetics of body size and related characters. I. Selection of small and large races of the laboratory mouse. Am Nat 78:142–157
Maden M, Ong DE, Summerbell D, Chytil F (1989) The role of retinoid-binding proteins in the generation of pattern in the developing limb, the regenerating limb and the nervous system. Development 107(Suppl):109–119
Manenti G, Galvan A, Pettinicchio A, Trincucci G, Spada E et al (2009) Mouse genome-wide association mapping needs linkage analysis to avoid false-positive loci. PLoS Genet 5:e1000331
Manly KF, Olson JM (1999) Overview of QTL mapping software and introduction to map manager QT. Mamm Genome 10:327–334
Masinde GL, Li X, Gu W, Davidson H, Mohan S et al (2001) Identification of wound healing/regeneration quantitative trait loci (QTL) at multiple time points that explain seventy percent of variance in (MRL/MpJ and SJL/J) mice F2 population. Genome Res 11:2027–2033
McBrearty BA, Clark LD, Zhang XM, Blankenhorn EP, Heber-Katz E (1998) Genetic analysis of a mammalian wound-healing trait. Proc Natl Acad Sci USA 95:11792–11797
Murphy ER, Roths JB (1978) Autoimmunity and lymphoproliferation: induction by mutant gene Lpr, and acceleration by a male-associated factor in strain BXSB mice. Elsevier North Holland, New York
Nakamura T, Takeuchi K, Muraoka S, Takezoe H, Takahashi N et al (1999) A neurally enriched coronin-like protein, ClipinC, is a novel candidate for an actin cytoskeleton-cortical membrane-linking protein. J Biol Chem 274:13322–13327
Norgard EA, Jarvis JP, Roseman CC, Maxwell TJ, Kenney-Hunt JP et al (2009) Replication of long-bone length QTL in the F9–F10 LG, SM advanced intercross. Mamm Genome 20:224–235
Reber-Muller S, Streitwolf-Engel R, Yanze N, Schmid V, Stierwald M et al (2006) BMP2/4 and BMP5–8 in jellyfish development and transdifferentiation. Int J Dev Biol 50:377–384
Rodriguez OC, Cheney RE (2002) Human myosin-Vc is a novel class V myosin expressed in epithelial cells. J Cell Sci 115:991–1004
Rodriguez OC, Schaefer AW, Mandato CA, Forscher P, Bement WM et al (2003) Conserved microtubule-actin interactions in cell movement and morphogenesis. Nat Cell Biol 5:599–609
Roesch A, Becker B, Schneider-Brachert W, Hagen I, Landthaler M et al (2006) Re-expression of the retinoblastoma-binding protein 2-homolog 1 reveals tumor-suppressive functions in highly metastatic melanoma cells. J Invest Dermatol 126:1850–1859
Stocum DL (1984) The urodele limb regeneration blastema. Determination and organization of the morphogenetic field. Differentiation 27:13–28
Ulrich MM, Verkerk M, Reijnen L, Vlig M, van den Bogaerdt AJ et al (2007) Expression profile of proteins involved in scar formation in the healing process of full-thickness excisional wounds in the porcine model. Wound Repair Regen 15:482–490
Wang S, Basten CJ, Zeng ZB (2009) Windows QTL Cartographer 2.5. Department of Statistics, North Carolina State University, Raleigh, NC
Woods A, James CG, Wang G, Dupuis H, Beier F (2009) Control of chondrocyte gene expression by actin dynamics: a novel role of cholesterol/roralpha signaling in endochondral bone growth. J Cell Mol Med
Yu H, Mohan S, Masinde GL, Baylink DJ (2005) Mapping the dominant wound healing and soft tissue regeneration QTL in MRL × CAST. Mamm Genome 16:918–924
Yu H, Baylink DJ, Masinde GL, Li R, Nguyen B et al (2007) Mouse chromosome 9 quantitative trait loci for soft tissue regeneration: congenic analysis and fine mapping. Wound Repair Regen 15:922–927
Zeng ZB (1993) Theoretical basis for separation of multiple linked gene effects in mapping quantitative trait loci. Proc Natl Acad Sci USA 90:10972–10976
Zeng ZB (1994) Precision mapping of quantitative trait loci. Genetics 136:1457–1468
Zhao P, Hoffman EP (2004) Embryonic myogenesis pathways in muscle regeneration. Dev Dyn 229:380–392
Acknowledgments
This study was supported by a grant from NIH, NIGMS GM073226, a grant from the Commonwealth of Pennsylvania Universal Research Enrichment Program, and an NCI Cancer Center Grant (P30 CA10815) to the Wistar Institute. This study was also supported by the Genomics and Animal Wistar Core Facilities. We thank Abhishek Kulkarni for his help in the linkage analysis.
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Blankenhorn, E.P., Bryan, G., Kossenkov, A.V. et al. Genetic loci that regulate healing and regeneration in LG/J and SM/J mice. Mamm Genome 20, 720–733 (2009). https://doi.org/10.1007/s00335-009-9216-3
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DOI: https://doi.org/10.1007/s00335-009-9216-3