Genetic analysis of a mammalian wound-healing trait

Abstract

Wound healing of mammalian tissue is an essential process in the maintenance of body integrity. The general mechanism of wound healing usually studied in adult mammals is repair, in contrast to the regeneration seen in more primitive vertebrates. We recently have discovered that MRL͞MpJ mice, unlike all other strains of mice tested, undergo rapid and complete wound closure that resembles regeneration. Specifically, through-and-through surgical ear hole wounds close without scarring in <4 weeks with normal gross and microanatomic architecture, including chondrogenesis. We also demonstrated that this healing is a heritable trait in inbred mice. In this study, we present results pertaining to its genetic control in progeny segregating for this phenotype. To identify the genetic loci that control the wound closure process, a genome-wide scan was performed on (MRL͞MpJ-Fas lpr ؋ C57BL͞6)F2 and backcross populations. In the primary screens of these populations, quantitative trait loci that control the extent of wound closure were detected on chromosomes 8, 12, and 15 and at two separate locations on chromosome 13. Evidence of further genetic control of healing was found on chromosome 7. All alleles that contribute to full wound closure are derived from the MRL͞MpJ-Fas lpr parent except for the quantitative trait locus on chromosome 8, which is derived from C57BL͞6.

Heart regeneration in adult MRL mice

“…This striking phenotype was first observed in the MRL mouse's ability to completely close through-and-through ear holes without scarring, to form a blastema, and to replace lost cartilage (19,20), a phenomenon similar to that seen during amphibian limb regeneration (2,3). In the present study, after right ventricular cryoinjury, the C57BL͞6 mouse healed with massive scarring and little if any new cardiomyocytes.…”

“…Furthermore, we have mapped the genes involved, identified a minimum of six different loci on five chromosomes, and shown that this is a complex multigenic trait (19,20).…”

Fine-mapping quantitative trait loci affecting murine external ear tissue regeneration in the LG/J by SM/J advanced intercross line

“…To identify genes associated with multigenic ear hole closure, linkage mapping studies have been conducted in a number of different MRL F2 intercrosses, including MRL Â C57BL/6 (B6) (McBrearty et al, 1998;Blankenhorn et al, 2003), MRL Â CAST/EiJ Yu et al, 2005) and MRL Â SJL/J (Masinde et al, 2001). MRL mice were originally bred from a series of crosses of four mouse strains (Murphy and Roths, 1978), AKR/J, C3H/HeDi, C57BL/6J, 65 and two final backcrosses with LG/J (LG).…”

Ability of Trichloroethylene Metabolite to Promote Immune Pathology is Strain-Specific

“…FasL expression on the cell surface can be regulated by cleavage of membrane-bound FasL into soluble FasL (sFasL) by MMP-7 and MMP-3 . Unlike C3H/HeJ mice, MRL +/+ mice apparently have a propensity to produce certain metalloproteinases (Gourevitch et al, 2003), which has been linked to their unusual capacity for wound healing (McBrearty et al 1998). It is possible that their propensity to produce metalloproteinases may also play a role in the autoimmune-proneness of MRL +/+ mice.…”