Neonatal lethality of mouse A/J-7SM consomic strain is caused by an insertion mutation in the Dchs1 gene.

Homosomic mice of the A/J-7SM consomic mouse strain that introduced the entire chromosome 7 (Chr 7) of SM/J into the A/J strain exhibited neonatal lethality. We tentatively maintained segregating inbred strains (A/J-7ASM and A/J-7DSM) in which the central portion of Chr 7 was heterozygous for the A/J and SM/J strains, and the centromeric and telomeric sides of Chr 7 were homozygous for the SM/J strain, instead of the A/J-7SM strain. Based on the chromosomal constitution of Chr 7 in A/J-7ASM and A/J-7DSM mice, the causative gene for neonatal lethality in homosomic mice was suggested to be located within an approximately 1.620 Mb region between D7Mit125 (104.879 Mb) and D7Mit355 (106.499 Mb) on Chr 7. RT-PCR analysis revealed that homosomic mice lacked dachsous cadherin-related 1 (Dchs1), which is located within the D7Mit125 to D7Mit355 region and functions in the regulation of planar cell polarity. Screening for mutations in Dchs1 indicated that homosomic mice possessed an early transposable (ETn)-like sequence in intron 1 of Dchs1. Moreover, an allelism test between Dchs1 ETn-like-insertion alleles detected in homosomic mice and CRISPR/Cas9-induced Dchs1 deletion alleles revealed that Dchs1 is a causative gene for neonatal lethality in homosomic mice. Based on these results, we concluded that in the A/J-7SM strain, ETn-like elements were inserted into intron 1 of SM/J-derived Dchs1 during strain development, which dramatically reduced Dchs1 expression, thus resulting in neonatal lethality in homosomic mice. Additionally, it was suggested that the timing of lethality in Dchs1 mutant mice is influenced by the genetic background.

Genetic analysis of abdominal fat distribution in SM/J and A/J mice.

Each abdominal fat depot, such as mesenteric or epididymal, differently contributes to the development of insulin resistance. The aim of this study was to identify the genetic regions that contribute to fat accumulation in epididymal/mesenteric fat and to examine whether or not the genetic regions that affect glucose metabolism and body fat distribution are coincident. We previously mapped a major quantitative trait locus (QTL) (T2dm2sa) for impaired glucose tolerance on chromosome 2 and revealed that SM.A-T2dm2sa congenic mice showed not only glucose tolerance but also fat accumulation. In the present study, to identify the loci/genes that control the accumulation of abdominal fat, we performed QTL analyses of epididymal/mesenteric fat weight by using (A/J x SM.A-T2dm2sa)F2 mice in which the effect of T2dm2sa was excluded. As a result, two highly significant QTLs for mesenteric fat, as well as three significant QTLs for epididymal/mesenteric fat, were mapped on the different chromosomal regions. This suggests that the fat accumulations in individual fat depots are controlled by distinct genomic regions. Our comparison of these QTLs for abdominal fat distribution with those for glucose metabolism revealed that the major genetic factors affecting body fat distribution do not coincide with genetic factors affecting glucose metabolism in (A/J x SM.A-T2dm2sa)F2.

Mouse NC/Jic strain provides novel insights into host genetic factors for malaria research.

Malaria is caused by Plasmodium parasites and is one of the most life-threatening infectious diseases in humans. Infection can result in severe complications such as cerebral malaria, acute lung injury/acute respiratory distress syndrome, and acute renal injury. These complications are mainly caused by P. falciparum infection and are major causes of death associated with malaria. There are a few species of rodent-infective malaria parasites, and mice infected with such parasites are now widely used for screening candidate drugs and vaccines and for studying host immune responses and pathogenesis associated with disease-related complications. We found that mice of the NC/Jic strain infected with rodent malarial parasites exhibit distinctive disease-related complications such as cerebral malaria and nephrotic syndrome, in addition to a rapid increase in parasitemia. Here, we focus on the analysis of host genetic factors that affect malarial pathogenesis and describe the characteristic features, utility, and future prospects for exploitation of the NC/Jic strain as a novel mouse model for malaria research.

Quantitative trait loci for impaired glucose tolerance in nondiabetic SM/J and A/J mice.

The SMXA-5 recombinant inbred strain, which was established from nondiabetic parental SM/J and A/J mice, develops diabetic phenotypes such as impaired glucose tolerance. The combination of diabetogenic genes in the SM/J and A/J genomes impairs glucose tolerance in SMXA-5 mice. Using (SM/J x SMXA-5)F2 mice fed a high-fat diet, we previously detected a diabetogenic locus, T2dm2sa, on chromosome (Chr) 2. The A/J allele at this locus is diabetogenic. The SM.A-T2dm2sa congenic mouse, in which the Chr 2 region of A/J including T2dm2sa was introgressed into SM/J, showed obviously impaired glucose tolerance. These results indicate that SM.A-T2dm2sa mice develop diabetogenic traits due to T2dm2sa with the A/J allele and unknown diabetogenic loci with the SM/J allele. The aim of this study was to dissect these unknown loci, using quantitative trait locus (QTL) analysis in the (A/J x SM.A-T2dm2sa) F2 intercross fed a high-fat diet. The results revealed a highly significant QTL, T2dm4sa, for glucose tolerance on Chr 6 and a significant QTL, T2dm5sa, for glucose tolerance on Chr 11. These loci with the SM/J allele were diabetogenic. The diabetogenic effect of T2dm4sa or T2dm5sa was verified by the impairment of glucose tolerance in the A/J-6(SM) or A/J-11(SM) consomic strain, in which Chr 6 or Chr 11 of SM/J is introgressed into A/J, respectively. These results demonstrate that diabetogenic loci exist in the genomes of nondiabetic A/J and SM/J mice and suggest that T2dm2sa with the A/J allele and T2dm4sa and/or T2dm5sa with the SM/J allele elicit impaired glucose tolerance in SM.A-T2dm2sa mice.