The Japanese Wild-Derived Inbred Mouse Strain, MSM/Ms in Cancer Research.

Kazuhiro Okumura,Eriko Isogai,Yuichi Wakabayashi,Megumi Saito

doi:10.3390/cancers13051026

Abstract

Simple SummarySince human studies on tumor susceptibility alleles require vast numbers of DNA samples from both cancer patients and well-matched controls, their investigation and identification in humans have been complemented using mouse models. However, a number of confounding factors are associated with this type of research, including heterogeneity, weak genetic interactions, and lifestyle habits. Inbred strains relatively recently established from wild mice are often more resistant to carcinogenic stimulation and various pathogens than standard inbred mouse strains. A Japanese wild-derived inbred mouse strain, MSM/Ms has been used to map tumor resistance loci as well as other Quantitative Trait Loci (QTL) in Japan. Furthermore, genetic tools have been developed with MSM/Ms. MSM/Ms genomic sequences are currently available, which have greatly promoted the identification of tumor resistance loci as well as genes controlling quantitative variations and provide a more detailed understanding of gene function. MSM/Ms is a unique inbred mouse strain derived from the Japanese wild mouse, Mus musculus molossinus, which has been approximately 1 million years genetically distant from standard inbred mouse strains mainly derived from M. m. domesticus. Due to its genetic divergence, MSM/Ms has been broadly used in linkage studies. A bacterial artificial chromosome (BAC) library was constructed for the MSM/Ms genome, and sequence analysis of the MSM/Ms genome showed approximately 1% of nucleotides differed from those in the commonly used inbred mouse strain, C57BL/6J. Therefore, MSM/Ms mice are thought to be useful for functional genome studies. MSM/Ms mice show unique characteristics of phenotypes, including its smaller body size, resistance to high-fat-diet-induced diabetes, high locomotive activity, and resistance to age-onset hearing loss, inflammation, and tumorigenesis, which are distinct from those of common inbred mouse strains. Furthermore, ES (Embryonic Stem) cell lines established from MSM/Ms allow the MSM/Ms genome to be genetically manipulated. Therefore, genomic and phenotypic analyses of MSM/Ms reveal novel insights into gene functions that were previously not obtained from research on common laboratory strains. Tumorigenesis-related MSM/Ms-specific genetic traits have been intensively investigated in Japan. Furthermore, radiation-induced thymic lymphomas and chemically-induced skin tumors have been extensively examined using MSM/Ms.

Highlights

19 prolonged the latency of the development of thymic lymphoma and the survival of the mice (Thyls4, Figure 1). These results indicated that BALB/c alleles in the Thyls4 region conferred resistance to radiation-induced thymic lymphomas and MSM alleles in that region conferred susceptibility on p53+/− background
Kominami and colleagues performed a genome-wide LOH analysis of radiationinduced thymic lymphomas obtained from F1 mice between BALB/c and MSM/Ms mice and backcross mice that are heterozygous for several chromosomes
Bcl11b+/+ p53+/− mice; the wild-type Bcl11b allele was retained and expressed in the majority of lymphomas [49]. These findings suggested that Bcl11b was haploinsufficient for the suppression of thymic lymphomagenesis in p53+/− mice, namely a condition under which the functional loss of only one allele was enough to confer an advantage for tumorigenesis

Summary

Introduction

A previous study reported the presence of the Skts locus in an intercross of several inbred mouse strains, like the collaborative cross recently performed [13]. A number of skin tumor modifier loci besides the Skts series were identified in standard inbred mouse strains and wild-derived inbred mouse strains. Psl were reported to be modifiers of DMBA/TPA induced skin tumors in backcross mice between commonly used inbred mouse strains [15,16]. Skts-fp 1-3 were reported to be modifiers of DMBA/TPA-induced skin tumors in backcross mice using PWK mice which is a wild-derived inbred mouse strain [17]. These genomic sequence differences make phenotypes of MSM/Ms mice very different from those of commonly used inbred mouse strains; they have a smaller body. Genomic and phenotypic analyses of MSM/Ms reveal novel insights into gene function that have not been possible using common laboratory strains

Identification of Tumor Resistance Loci

Genetic Analysis of the LOH Region

Tumor Resistance Loci on Chromosome 7

Tumor Resistance Loci on Chromosome 4

Findings

Conclusions