Genetic loci that regulate healing and regeneration in LG/J and SM/J mice

Abstract

MRL mice display unusual healing properties. When MRL ear pinnae are hole punched, the holes close completely without scarring, with re-growth of cartilage, and reappearance of both hair follicles and sebaceous glands. Studies using (MRL/lpr x 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 >200 polymorphic markers. As we previously observed for MRL and (MRL x 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 (QTL) on chromosomes (chr) 9, 10, 11, and 15. The heal QTL on chrs 11 and 15 were linked to differential healing primarily in male animals, whereas QTL 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 x SM/J showed that loci on chrs 9, 11 and 15 co-localized with those seen in previous MRL crosses, whereas the locus on chr 10 was not seen before and was is contributed by SM/J.

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

“…In the current study, real progress has been made in narrowing the quantitative trait intervals by use of the (LG,SM) F34 AIL. An important feature of the present work is that QTLs on chromosomes 9, 10, 11, 14 and 18 discovered in earlier studies (Blankenhorn et al, 2009;Cheverud et al, 2012) were confirmed in the AI line, lending further credence to their role in regenerative healing. New QTLs have been identified on chromosomes 1, 7, 12 and 13 in this study.…”

“…Gene expression studies for ear hole closure in LG/J and SM/J mice were previously reported (Blankenhorn et al, 2009). RNA samples were prepared in triplicate from day 0 ear holes and from day 7 ear hole donuts from LG/J and SM/J female mice (3 mm circular blastemas formed around the hole punch).…”

“…Only one of these parental lines, LG, which contributed 75% of the MRL genome, has been shown to have a regenerative ear hole response (Kench et al, 1999;Li et al, 2010). Recently, a linkage study using LG/J Â SM/J (SM) F2 intercrosses identified multiple quantitative trait loci (QTL) that regulate wound healing with regeneration (Blankenhorn et al, 2009). Further analysis of LG,SM QTL show that when compared with the QTL identified in MRL crosses, there are both shared and unique loci (Cheverud et al, 2012).…”

Genetic Control of Susceptibility to Candida albicans in SM/J Mice

“…Whether SM/J mice possess impaired emergency myelopoiesis remains to be ascertained, and it will entail challenging this strain with other pathogens. Thus far, SM/J mice have been deemed susceptible to blood-stage malaria caused by Plasmodium chabaudi (68), and they are considered a non-healer strain when the ear pinnae are wounded (69). The wound-healing trait is controlled by multiple loci, including a locus Heal4 mapping to distal chromosome 15 and overlapping with Carg5.…”

Hypomorphic sialidase expression decreases serum cholesterol by downregulation of VLDL production in mice

“…This promoter mutation creates a binding site for a transcriptional repressor, Nkx3.2, resulting in reduced gene expression ( 56 ). SM/J mice, however, harbor mutations in a number of other genes ( 57,58 ), complicating analysis of the physiological consequences of low sialidase. We have therefore isolated this mutation from the SM/J mice by backcrossing onto a C57Bl/6 genetic background, generating a hypomorphic sialidase mouse, named B6.SM, which has reduced sialidase protein levels and activity.…”