BXD Recombinant Inbred Mice as a Model to Study Neurotoxicity

BXD recombinant inbred (RI) lines represent a genetic reference population derived from a cross between C57BL/6J mice (B6) and DBA/2J mice (D2), which through meiotic recombination events possesses recombinant chromosomes containing B6 or D2 haplotype segments. The quantitative trait loci (QTLs) are the locations of segregating genetic polymorphisms and are fundamental to understanding genetic diversity in human disease susceptibility and severity. QTL mapping represents the typical approach for identifying naturally occurring polymorphisms that influence complex phenotypes. In this process, genotypic values at markers of known genomic locations are associated with phenotypic values measured in a segregating population. Indeed, BXD RI strains provide a powerful tool to study neurotoxicity induced by different substances. In this review, we describe the use of BXD RI lines to understand the underlying mechanisms of neurotoxicity in response to ethanol and cocaine, as well as metals and pesticide exposures.

Recombinant Inbred Mice as Models for Experimental Precision Medicine and Biology

Recombinant inbred rodents form immortal genome-types that can be resampled deeply at many stages, in both sexes, and under multiple experimental conditions to model genome-environment interactions and to test genome-phenome predictions. This allows for experimental precision medicine, for which sophisticated causal models of complex interactions among DNA variants, phenotype variants at many levels, and innumerable environmental factors are required. Large families and populations of isogenic lines of mice and rats are now available and have been used across fields of biology. We will use the BXD recombinant inbred family and their derived diallel cross population as an example for predictive, experimental precision medicine and biology.

P097 Depletion of delta-like ligand 4 (Dll4) contributes to the alteration of secretory progenitor differentiation in SAMP1/YitFc mice with Crohn’s disease-like ileitis

Background When the intestinal epithelium would be exposed to harmful substances, mucosal damage can be occurred and followed by epithelial restoration with regenerative epithelium derived from intestinal stem cells (ISCs). Crohn’s disease (CD) is characterised by chronic mucosal damage and ulceration predominantly involved in the ileum. Thus, we hypothesised that epithelial regeneration in CD might be impaired due to the dysfunction of ileal ISCs or its niche. Methods SAMP1/YitFcsI (SAMP1) mice are recombinant-inbred mice that spontaneously develop ileitis resembling human CD. Alterations in the crypt-villus structure, epithelial differentiation, organoid formation ability, and niche signalling pathways in the ileum of 10- to 14-week-old SAMP1 mice were analysed and compared with age-matched AKR mice. Results In the ileum of SAMP1 mice, the depth of the crypts increased and the surface area of the villi decreased. While the number of ISCs in the ileal crypts did not differ between SAMP1 and AKR mice. The number of Paneth cells decreased and the number of transient amplifying cells increased. The organoid formation ability of the ileal crypts of SAMP1 mice decreased significantly compared with that of AKR mice. RNA-seq revealed a differential gene expression pattern of ileal crypts of SAMP1 mice compared with those of AKR mice. Among the ISCs and niche signalling, the expression of delta-like ligand 4 (Dll4) was significantly decreased and the expression of genes associated with Notch signalling tended to decrease in the ileal crypts of SAMP1 mice. Conclusion The characteristic ileitis in SAMP1 mice may be caused by impaired Dll4-Notch signalling.