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Strategy to identify promising mouse lines for airway challenge

The influence of genetic and environmental factors on the susceptibility of disease is still studied intensively. The standard systematic primary phenotyping procedure in the German Mouse Clinic provides (among many other data) original data from allergy and immunology screens under standard husbandry conditions. The data sets of hundreds of mutant mouse lines were used by Horsch et al. to identify new potential inflammatory models. However, the genetic predisposition for diseases is often only revealed if environmental factors challenge the organism. Since airway inflammation challenge experiments are cost intensive and time consuming Marion Horsch, Juan Antonio Aguilar-Pimentel and their colleagues were looking for a strategy to decide whether the invest will be indicated.
They identified expression profiling in combination with published gene function data as a valuable tool because the analysis of the expression profiles before the challenge already shows reliably if there is an association with immune response.

Three selected mouse models are presented in the publication. The selected mutant mouse lines carried loss-of-function alleles in either cytochrome c oxidase subunit 4 isoform 2 (Cox4i2), interferon-induced protein with tetratricopeptide repeats 2 (Ifit2), or PR domain containing 11 (Prdm11). This mice under steady-state conditions did not shows hits in the immunological or Allergic screening parameters of the GMC but the gene function annotation in combination with the observed regulated genes in expression profiling gave a hint towards possible involvement in airway inflammatory processes. To induce an airway inflammatory response, the mutant mouse lines underwent High Throughput Screening challenge procedure using ovalbumin (OVA).

The phenotyping results under OVA airway challenge conditions revealed genotype-specific alterations of plasma immunoglobulin isotype levels (in Ifit2 mutant line), cell distributions in the lung (in Prdm11 mutant line), and no changes for Cox4i2.

The authors confirm that the gene expression profiles changes (number / function of genes) from unchallenged mice correlated with the post challenge in vivo results (cells / immunoglobulin isotypes).
This data shows that gene expression profiling in combination with gene function information is a good strategy to identify mutant mouse lines that may show phenotypes under challenges conditions that otherwise will be hidden if there is not an environmental trigger, with this strategy we cannot just reduce costs and time but as well reduce the animal use in animal experiments.

Horsch M, Aguilar-Pimentel JA, Bönisch C, Côme C, Kolster-Fog C, Jensen KT, et al. (2015) Cox4i2, Ifit2, and Prdm11 Mutant Mice: Effective Selection of Genes Predisposing to an Altered Airway Inflammatory Response from a Large Compendium of Mutant Mouse Lines. PLoS ONE 10(8): e0134503. doi:10.1371/journal.pone.0134503