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Summary of Currently Available Mouse Models

Ami Ito, Namiko Ito, Kimie Niimi, Takashi Arai, and Eiki Takahashi

RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan

1.1 Introduction

It is estimated that laboratory mice comprise more than 80% of the animals used in research. Researchers have nearly 100 years of experience working with mice in the field in settings such as commercial rodent production sites, laboratories, academic institutions, and pharmaceutical companies and have also performed resource studies. Mice require relatively little space and do not have complex dietary needs. They are easy to physically manipulate and relatively inexpensive compared to other laboratory animals. Although this is problematic with some species, mice can be inbred, which enables inclusion of littermates as controls and production of large number of animals. Production of inbred strains means that their backgrounds can be defined. Given ideal conditions, mice can produce at least four generations in a year, meaning that multiple generations can be produced rapidly and followed for experimental purposes. As small mammals, they have a limited lifespan, which facilitates aging and multigenerational studies.

Mice were the first mammals after humans to have their genome sequenced [1]. As there is approximately 85% homology between the mouse and human genomes, any given gene is most likely present in both the mouse and human genomes and will generally have a similar function [1]. This allows mice to serve as models of many human conditions and, more importantly, allows us to study basic mammalian genetics and other conserved systems in mammalian cells.

The study of mutant mice has evolved from the exploration of the collections of the spontaneous coat color mutants maintained by nineteenth century mouse fanciers to the advent of several methods of directed manipulation of the mouse genome. A further explanation for the dominance of the mouse in research is the robustness of their embryos. These may be cryopreserved and cultured from the one-cell stage to the post-implantation stage. Advances in molecular technologies have improved our ability to create mouse models of human disease by means of transgenesis, targeted mutagenesis, and the CRISPR/Cas9 system. These mutations continue to provide valuable research tools for the study of the functions of genes within the entire organism. Today, there are repositories of genetically mutant mice located around the world that provide scientists with access to models of many diseases, contributing substantially to our understanding of both basic biological pathways and disease mechanisms.

Figure 1.1 Mice used in the laboratory are derived from a variety of sources.

This chapter describes the history of laboratory mice; the types of mouse strains available; the handling of mouse colonies, mouse cell lines, and strains; and the use of mouse models in preclinical studies.

1.2 Origin and History of Laboratory Mice

Mice currently used in the laboratory are domesticated animals. Laboratory mice are fatter, slower, less aggressive, and more amenable to handling than their wild-caught counterparts. Mice likely originated on the Indian subcontinent and spread throughout the world with agriculture and human movement [2] (Figure 1.1). Contemporary mice have genetic contributions from both Mus musculus ssp. musculus and Mus musculus ssp. domesticus, and evidence indicates that Mus musculus ssp. molossinus and Mus musculus ssp. castaneus made smaller contributions. Therefore, mice should not be referred to by their species name but rather as laboratory mice or by a specific strain or stock name. Additionally, some recently developed laboratory mouse strains are derived wholly from other Mus species or other subspecies, such as Mus spretus.

The source of many of the mouse strains currently in use is the mouse colony established by Miss Abbie Lathrop (1868-1918) in her small white farmhouse in Granby, Massachusetts [3]. Dr. William E. Castle (1867-1962), a pioneer in mouse genetics, purchased some of Lathrop's mice and trained Dr. Clarence. C. Little (1888-1971), the founder of the Jackson Laboratory. Dr. Little bred C57BL/6 from Lathrop's mouse number 57. The resulting C57BL/6 became the most frequently used strain of laboratory mice.

1.3 Laboratory Mouse Strains

1.3.1 Wild-Derived Mice

Wild-derived mice are descendants of mice originally caught in the wild. The available wild-derived strains are M. musculus ssp. musculus, M. musculus ssp. domesticus, M. musculus ssp. molossinus, M. musculus ssp. castaneus, Mus caroli, Mus hortulames, Mus praetextus, Mus pahari, and Mus spretus (Table 1.1). Wild-derived mice are genetically distinct from common laboratory mice in a number of complex phenotypic characteristics and are valuable tools for genetic evolution and systematics research. They enable mapping of both the single-gene traits and quantitative trait loci (QTL) contributing to complex phenotypes.

Table 1.1 Origin of wild-derived inbred strains.a)

Source: Data from Jax Mice Database - Wild-derived Inbred Website.

M., Mus.

a) https://www.jax.org/search?q.

1.3.2 Inbred Mice

Strains can be termed inbred if they have been mated brother?×?sister for 20 or more consecutive generations, and individuals of the strain can be traced to a single ancestral pair at the twentieth or subsequent generation. At this point, the individuals' genomes will, on average, have only 0.01 residual heterozygosity (excluding any genetic drift) and can, for most purposes, be regarded as genetically identical. Inbred mouse strains exhibit specific characteristics (Table 1.2) and provide a uniform genetic background for accurate phenotypic evaluation.

1.3.3 Hybrid Mice

Mice that are the progeny of two inbred strains, crossed in the same direction, are genetically identical and can be designated using uppercase abbreviations of the two parents (maternal strain listed first), followed by F1. Note that the reciprocal F1 hybrids are not genetically identical and their designations are, therefore, different.

Examples

• D2B6F1: Mouse that is the offspring of a DBA/2N mother and a C57BL6/J father. A full F1 designation is (DBA/2N x C57BL/6J)F1.
• B6D2F1: Mouse that is the offspring of a C57BL6/J mother and a DBA/2N father. A full F1 designation is (C57BL/6J x DBA/2N)F1.

For the sake of clarity, the full strain symbols of the above cases should be given in any publication when the hybrids or crosses are first referred to. If a hybrid were to be constructed using a substrain known to differ from the "standard" strain genetically and/or phenotypically, the substrain should be indicated in the hybrid symbol: e.g. C3H/HeSn = C3Sn. The approved abbreviations for common mouse strains are listed below:

• 129: 129 strains (may include subtype; e.g. 129S6 for strain 129S6/SvEvTac)
• A: A strains, except for Heston substrains
• A/He: A/He (Heston substrains)
• AK: AKR strains
• B6J: C57BL/6J substrains
• B6N: C57BL/6N substrains
• C: BALB/c strains
• cBy: BALB/cBy...