The MRL mouse is an inbred laboratory strain that was derived by selective breeding in 1960 from the rapidly growing LG/J (Large) strain. MRL mice grow to nearly twice the size of other commonly used mouse strains, display uncommonly robust healing and regeneration properties, and express later onset autoimmune traits similar to Systemic Lupus Erythematosis. The regeneration trait (heal) in the MRL mouse maps to 14–20 quantitative trait loci and the autoimmune traits map to 5–8 loci. In this paper we report the metabolic and biochemical features that characterize the adult MRL mouse and distinguish it from C57BL/6 control animals. We found that adult MRL mice have retained a number of features of embryonic metabolism that are normally lost during development in other strains. These include an emphasis on aerobic glycolytic energy metabolism, increased glutamate oxidation, and a reduced capacity for fatty acid oxidation. MRL tissues, including the heart, liver, and regenerating ear hole margins, showed considerable mitochondrial genetic and physiologic reserve, decreased mitochondrial transmembrane potential (ΔΨm), decreased reactive oxygen species (ROS), and decreased oxidative phosphorylation, yet increased mitochondrial DNA and protein content. The discovery of embryonic metabolic features led us to look for cells that express markers of embryonic stem cells. We found that the adult MRL mouse has retained populations of cells that express the stem cell markers Nanog, Islet-1, and Sox2. These are present in the heart at baseline and highly induced after myocardial injury. The retention of embryonic features of metabolism in adulthood is rare in mammals. The MRL mouse provides a unique experimental window into the relationship between metabolism, stem cell biology, and regeneration.
BackgroundMouse fetuses up to 16 day of embryonic development and nude (Foxn1- deficient) mice are examples of animals that undergo regenerative (scar-free) skin healing. The expression of transcription factor Foxn1 in the epidermis of mouse fetuses begins at embryonic day 16.5 which coincides with the transition point from scar-free to scar-forming skin wound healing. In the present study, we tested the hypothesis that Foxn1 expression in the skin is an essential condition to establish the adult skin phenotype and that Foxn1 inactivity in nude mice keeps skin in the immature stage resembling the phenomena of neoteny.ResultsUninjured skin of adult C57BL/6J (B6) mice, mouse fetuses at days 14 (E14) and 18 (E18) of embryonic development and B6.Cg-Foxn1 nu (nude) mice were characterized for their gene expression profiles by RNA sequencing that was validated through qRT-PCR, Western Blot and immunohistochemistry. Differentially regulated genes indicated that nude mice were more similar to E14 (model of regenerative healing) and B6 were more similar to E18 (model of reparative healing). The up-regulated genes in nude and E14 mice were associated with tissue remodeling, cytoskeletal rearrangement, wound healing and immune response, whereas the down-regulated genes were associated with differentiation. E14 and nude mice exhibit prominent up-regulation of keratin (Krt23, -73, -82, -16, -17), involucrin (Ivl) and filaggrin (Flg2) genes. The transcription factors associated with the Hox genes known to specify cell fate during embryonic development and promote embryonic stem cells differentiation were down-regulated in both nude and E14. Among the genes enriched in the nude skin but not shared with E14 fetuses were members of the Wnt and matrix metalloproteinases (Mmps) families whereas Bmp and Notch related genes were down-regulated.ConclusionsIn summary, Foxn1 appears to be a pivotal control element of the developmental program and skin maturation. Nude mice may be considered as a model of neoteny among mammals. The resemblance of gene expression profiles in the skin of both nude and E14 mice are direct or indirect consequences of the Foxn1 deficiency. Foxn1 appears to regulate the balance between cell proliferation and differentiation and its inactivity creates a pro-regenerative environment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3401-z) contains supplementary material, which is available to authorized users.
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