Japanese Fancy Mouse Research Articles

JF1/B6F1 Ngly1-/- mouse as an isogenic animal model of NGLY1 deficiency.

N-Glycanase 1 (NGLY1) deficiency is a congenital disorder caused by mutations in the NGLY1 gene. Because systemic Ngly1−/− mice with a C57BL/6 (B6) background are embryonically lethal, studies on the mechanism of NGLY1 deficiency using mice have been problematic. In this study, B6-Ngly1−/+ mice were crossed with Japanese wild mice-originated Japanese fancy mouse 1 (JF1) mice to produce viable F2 Ngly1−/− mice from (JF1×B6)F1 Ngly1−/+ mice. Systemic Ngly1−/− mice with a JF1 mouse background were also embryonically lethal. Hybrid F1 Ngly1−/− (JF1/B6F1) mice, however, showed developmental delay and motor dysfunction, similar to that in human patients. JF1/B6F1 Ngly1−/− mice showed increased levels of plasma and urinary aspartylglycosamine, a potential biomarker for NGLY1 deficiency. JF1/B6F1 Ngly1−/− mice are a useful isogenic animal model for the preclinical testing of therapeutic options and understanding the precise pathogenic mechanisms responsible for NGLY1 deficiency.

Nested retrotransposition in the East Asian mouse genome causes the classical nonagouti mutation

Black coat color (nonagouti) is a widespread classical mutation in laboratory mouse strains. The intronic insertion of endogenous retrovirus VL30 in the nonagouti (a) allele of agouti gene was previously reported as the cause of the nonagouti phenotype. Here, we report agouti mouse strains from East Asia that carry the VL30 insertion, indicating that VL30 alone does not cause the nonagouti phenotype. We find that a rare type of endogenous retrovirus, β4, was integrated into the VL30 region at the a allele through nested retrotransposition, causing abnormal splicing. Targeted complete deletion of the β4 element restores agouti gene expression and agouti coat color, whereas deletion of β4 except for a single long terminal repeat results in black-and-tan coat color. Phylogenetic analyses show that the a allele and the β4 retrovirus originated from an East Asian mouse lineage most likely related to Japanese fancy mice. These findings reveal the causal mechanism and historic origin of the classical nonagouti mutation.

Morphofunctional evaluation of the testis, duration of spermatogenesis and spermatogenic efficiency in the Japanese fancy mouse (Mus musculus molossinus).

Japanese fancy mouse, mini mouse or pet mouse are common names used to refer to strains of mice that present with different colour varieties and coat types. Although many genetic studies that involve spotting phenotype based on the coat have been performed in these mice, there are no reports of quantitative data in the literature regarding testis structure and spermatogenic efficiency. Hence, in this study we researched testis function and spermatogenesis in the adult Japanese fancy mouse. The following values of 68 ± 6 mg and 0.94 ± 0.1% were obtained as mean testis weight and gonadosomatic index, respectively. In comparison with other investigated mice strains, the fancy mouse Leydig cell individual size was much smaller, resulting in higher numbers of these cells per gram of testis. As found for laboratory mice strains, as a result of the development of the acrosomic system, 12 stages of the seminiferous epithelium cycle have been described in this study. The combined frequencies of pre-meiotic and post-meiotic stages were respectively 24% and 64% and very similar to the laboratory mice. The more differentiated germ cell types marked at 1 h or 9 days after tritiated thymidine administration were preleptotene/leptotene and pachytene spermatocytes at the same stage (VIII). The mean duration of one spermatogenic cycle was 8.8 ± 0.01 days and the total length of spermatogenesis lasted 37.8 ± 0.01 days (4.5 cycles). A high number of germ cell apoptosis was evident during meiosis, resulting in lower Sertoli cell and spermatogenic efficiencies, when compared with laboratory mice strains.

Piebald mutation on a C57BL/6J background.

The classic piebald mutation in the endothelin receptor type B (Ednrb) gene was found on rolling Nagoya genetic background (PROD-s/s) mice with white coat spotting. To examine whether genetic background influenced the phenotype in the piebald mutant mice, we generated a congenic strain (B6.PROD-s/s), produced by repeated backcrosses to the C57BL/6J (B6) strain. Although B6.PROD-s/s mice showed white coat spotting, 7% of B6.PROD-s/s mice died between 2 and 5 weeks after birth due to megacolon. The PROD-s/s, s/s and Japanese fancy mouse 1 (JF1) strains, which also have piebald mutations on different genetic backgrounds with B6, showed only pigmentation defects without megacolon. In expression analyses, rectums of B6.PROD-s/s with megacolon mice showed ~5% of the level of Ednrb gene expression versus B6 mice. In histological analyses, aganglionosis was detected in the rectum of megacolon animals. The aganglionic rectum was thought to lead to severe constipation and intestinal blockage, resulting in megacolon. We also observed an abnormal intestinal flora, including a marked increase in Bacteroidaceae and Erysipelotrichaceae and a marked decrease in Lactobacillus and Clostridiales, likely inducing endotoxin production and a failure of the mucosal barrier system, leading ultimately to death. These results indicate that the genetic background plays a key role in the development of enteric ganglion neurons, controlled by the Ednrb gene, and that B6 has modifier gene (s) regarding aganglionosis.

Possible involvement of Hcn1 ion channel in learning and memory dysfunction in SAMP8 mice

The senescence-accelerated mouse prone 8 (SAMP8) strain exhibits age-related learning and memory deficits (LMD) at 2months of age. Combined linkage analysis of 264 F2 intercross SAMP8 × JF1 mice and RNA-seq analysis identified Hcn1 gene out of 29 genes in the LMD region on chromosome 13. Hcn1 in SAMP8 strain showed 15 times less polyglutamine repetition compared to Japanese fancy mouse 1 (JF1). Whole cell patch clamp analysis showed that Hcn1 ion conductivity was significantly lower in SAMP8 compared to that of JF1, which may be associated with learning and memory deficiency.

The ancestor of extant Japanese fancy mice contributed to the mosaic genomes of classical inbred strains.

Commonly used classical inbred mouse strains have mosaic genomes with sequences from different subspecific origins. Their genomes are derived predominantly from the Western European subspecies Mus musculus domesticus, with the remaining sequences derived mostly from the Japanese subspecies Mus musculus molossinus. However, it remains unknown how this intersubspecific genome introgression occurred during the establishment of classical inbred strains. In this study, we resequenced the genomes of two M. m. molossinus–derived inbred strains, MSM/Ms and JF1/Ms. MSM/Ms originated from Japanese wild mice, and the ancestry of JF1/Ms was originally found in Europe and then transferred to Japan. We compared the characteristics of these sequences to those of the C57BL/6J reference sequence and the recent data sets from the resequencing of 17 inbred strains in the Mouse Genome Project (MGP), and the results unequivocally show that genome introgression from M. m. molossinus into M. m. domesticus provided the primary framework for the mosaic genomes of classical inbred strains. Furthermore, the genomes of C57BL/6J and other classical inbred strains have long consecutive segments with extremely high similarity (>99.998%) to the JF1/Ms strain. In the early 20th century, Japanese waltzing mice with a morphological phenotype resembling that of JF1/Ms mice were often crossed with European fancy mice for early studies of “Mendelism,” which suggests that the ancestor of the extant JF1/Ms strain provided the origin of the M. m. molossinus genome in classical inbred strains and largely contributed to its intersubspecific genome diversity.

Anatomic Modifications in the Enteric Nervous System of JF1 Mice with the Classic Piebald Mutation

The Japanese Fancy Mouse 1 (JF1) has a characteristic coat color similar to a very old mutant, piebald. The mutation in JF1 and the classic piebald was previously thought to be the same recessive allele in the endothelin B receptor gene (Ednrb) according to the haplotype pattern, which is insufficient for this conclusion. In this study, we identified the same insertion of a retroposon-like element in intron 1 of the Ednrb gene in JF1 as in the classic piebald mutation by PCR. Further, we investigated whether the intestine shows neuronal intestinal malformations such as hypoganglionosis and immaturity of ganglion cells by histochemical staining. Though it has been assumed that the defect of neural crest-derived lineages is restricted to melanocytes in JF1, we found that the enteric innervation and neuronal density were impaired throughout the whole colon in JF1 mice.

Relationship of strain-dependent susceptibility to experimentally induced acute pancreatitis with regulation of Prss1 and Spink3 expression

To analyze susceptibility to acute pancreatitis, five mouse strains including Japanese Fancy Mouse 1 (JF1), C57BL/6J, BALB/c, CBA/J, and C3H/HeJ were treated with either a cholecystokinin analog, cerulein, or a choline-deficient, ethionine-supplemented (CDE) diet. The severity of acute pancreatitis induced by cerulein was highest in C3H/HeJ and CBA/J, moderate in BALB/c, and mildest in C57BL/6J and JF1. Basal protein expression levels of the serine protease inhibitor, Kazal type 3 (Spink3) were higher in JF1 and C57BL/6J mice than those of the other three strains under normal feeding conditions. After treatment with cerulein, expression level of Spink3 increased remarkably in JF1 and mildly in C57BL/6J, BALB/c, CBA/J, and C3H/HeJ strains. Increased proteinase, serine, 1 (Prss1) protein expression accompanied by increased trypsin activity with cerulein treatment was observed in susceptible strains such as CBA/J and C3H/HeJ. Similar results were obtained with a CDE diet. In the 3 kb Spink3 promoter region, 92 or 8 nucleotide changes were found in JF1 or C3H vs C57BL/6J, respectively, whereas in the Prss1 promoter region 39 or 46 nucleotide changes were found in JF1 or C3H vs C57BL/6J, respectively. These results suggest that regulation of Prss1 and Spink3 expression is involved in the susceptibility to experimentally induced pancreatitis. The JF1 strain, which is derived from the Japanese wild mouse, will be useful to examine new mechanisms that may not be found in other laboratory mouse strains.

Mouse Phenome Research: Implications of Genetic Background

Now that sequencing of the mouse genome has been completed, the function of each gene remains to be elucidated through phenotypic analysis. The "genetic background" (in which each gene functions) is defined as the genotype of all other related genes that may interact with the gene of interest, and therefore potentially influences the specific phenotype. To understand the nature and importance of genetic background on phenotypic expression of specific genes, it is necessary to know the origin and evolutionary history of the laboratory mouse genome. Molecular analysis has indicated that the fancy mice of Japan and Europe contributed significantly to the origin of today's laboratory mice. The genetic background of present-day laboratory mice varies by mouse strain, but is mainly derived from the European domesticus subspecies group and to a lesser degree from Asian mice, probably Japanese fancy mice, which belong to the musculus subspecies group. Inbred laboratory mouse strains are genetically uniform due to extensive inbreeding, and they have greatly contributed to the genetic analysis of many Mendelian traits. Meanwhile, for a variety of practical reasons, many transgenic and targeted mutant mice have been created in mice of mixed genetic backgrounds to elucidate the function of the genes, although efforts have been made to create inbred transgenic mice and targeted mutant mice with coisogenic embryonic stem cell lines. Inbred mouse strains have provided uniform genetic background for accurate evaluation of specific genes phenotypes, thus eliminating the phenotypic variations caused by mixed genetic backgrounds. However, the process of inbreeding and selection of various inbred strain characteristics has resulted in inadvertent selection of other undesirable genetic characteristics and mutations that may influence the genotype and preclude effective phenotypic analysis. Because many of the common inbred mouse stains have been established from relatively small gene pools, common inbred strains have limitations in their genetic polymorphisms and phenotypic variations. Wild-derived mouse strains can complement deficiencies of common inbred mouse strains, providing novel allelic variants and phenotypes. Although wild-derived strains are not as tame as the common laboratory strains, their genetic characteristics are attractive for the future study of gene function.

Regional variations in the distributions of small intestinal intraepithelial lymphocytes (IELs) in outbred laboratory mice ( Mus musculus domesticus) and the inbred strain of mice established from Japanese fancy mice ( Mus musculus molossinus)

Previously, we reported regional variations in small intestinal IELs of mice. In this study, we examined the regional variations of IELs in outbred laboratory mice (ddY: Mus musculus domesticus) and the inbred strain of mice established from Japanese fancy mice (JF1: Mus musculus molossinus). IELs were isolated from the proximal, middle and distal parts of the small intestine and analyzed by flow cytometry. The percentages of γδ T cells and αβ T cell subset of extrathymic origin were higher in the proximal part while the percentages of αβ T cell subset(s) of thymic origin were higher in the distal part in both ddY and JF1 mice. Such trends in regional variations of IELs were almost the same as those found in the inbred strains of laboratory mice in our previous reports. This strongly suggests that these regional variations of IELs may be common phenomena in Mus musculus species.

Genetic analysis of learning and memory deficits in senescence-accelerated mouse (SAM)

Genetic analysis of learning and memory deficits (LMD) in senescence-accelerated mouse P8 (SAMP8) was performed by cross-mating SAMP8 and Japanese Fancy Mouse 1 (JF1). The incidence of LMD in the F2 generation showed a 3:1 segregation ratio of mice with LMD to normal mice, and the incidence of LMD in the backcross generation of the F1 to JF1 parental strain was in agreement with a 1:1 ratio of mice with LMD to normal mice. Estimation of the number of genes involved in the development of LMD using Wright's formula showed that at least two to four genes are involved. These results suggest that the inheritance of LMD is polygenically controlled and that there may be a single major gene, but this locus is not sex-linked. Moreover, hormonal influence on the development of LMD in SAMP8 females is of a genotype-dependent manner.

Repeated Topical Challenge with Chemical Antigen Elicits Sustained Dermatitis in NC/Nga Mice in Specific-Pathogen-Free Condition

NC/Nga mice are known to develop skin lesions resembling to atopic dermatitis (AD) in conventional but not in specific-pathogen-free (SPF) condition. An epicutaneous application of 2,4-dinitrofluorobenzene (DNFB) increased skin thickness in C3H as well as NC/Nga mice in SPF environment, and the response was enlarged by repeating the challenge at weekly intervals. Although the skin reaction in C3H mice was ameliorated when the challenge was discontinued after the fifth application, the reaction in NC/Nga mice was sustained at least for 3 wk. Analyses of cytokine production by CD4+ cells from the draining lymph node proximal to the lesions revealed that, unlike C3H mice, NC/Nga mice fail to induce T helper 2 (Th2) cytokine interleukin-4 (IL-4), whereas the level of Th1 cytokine interferon-gamma in NC/Nga mice is equivalent to that of C3H mice. In addition, NC/Nga mice highly expressed IL-12, a cytokine-preventing formation of Th2 response, whereas C3H mice did not. Administration of anti-IL-12 antibody reduced duration of dermatitis in DNFB-treated NC/Nga mice. Taken together, our data suggest that IL-12 plays a role in the persistent skin reaction in NC/Nga mice. The action of IL-12 might be mediated by the decrease in IL-4 production.

Characterization of diabetes-related traits in MSM and JF1 mice on high-fat diet

We examined the effect of a high-fat diet on the diabetes-related traits of the Japanese Fancy mouse 1 (JF1), MSM, and C57BL/6J (B6J) mice. MSM and JF1 mice were derived from Mus musculus molossinus. B6J is a commonly used laboratory strain, with the vast majority of genome segments derived from Mus musculus domesticus and Mus musculus musculus, and is susceptible to high-fat diet–induced type 2 diabetes. None of the strains showed symptoms of diabetes or obesity when fed a laboratory chow diet. Under a high-fat diet, JF1 mice developed impaired glucose tolerance, hyperglycemia, hyperinsulinemia, and obesity. B6J mice fed a high-fat diet mildly developed these diabetes-related traits compared to JF1 mice fed a high-fat diet. JF1 mice fed a high-fat diet were classified as having type 2 diabetes and were susceptible to high-fat diet–induced diabetes and obesity. On the other hand, MSM mice were resistant to high-fat diet–induced diabetes. These results indicate that the JF1 strain, with its unique genetic origin, is a useful new animal model of high-fat diet–induced diabetes and obesity. Further investigations using JF1 mice will help to clarify the role of the high-fat diet on human diabetes and obesity.

Quantitative trait loci for age-related memory dysfunction in SAMP8 and JF1 mice

The senescence-accelerated mouse (SAM) P8 strain exhibits severe age-related learning and memory deficits (LMD) well before the median age of survival. As a first step to clarify the genes involved in this deterioration, we have performed genetic analysis of SAMP8 using the whole genome scan for quantitative trait loci (QTLs) specifying the impairment in step-through passive avoidance response with F2 intercrosses of SAMP8 exhibiting short retention time (RT) and Japanese Fancy Mouse 1 (JF1) derived from Japanese wild mouse ( Mus musculus molossinus) exhibiting normal long retention time. Genetic markers were typed at 113 loci spanning all chromosomes except the Y. Five loci have been identified with significant linkage to chromosomes 1, 12, 13 and 15 by interval mapping of 264 F2 mice. Three of them on chromosomes 1, 12, and 13 are due to SAMP8 background, while two of them on chromosome 15 are derived from JF1 background despite parental JF1 strain shows normal phenotype.

Genetic study of learning and memory deficits in SAMP8 mice

Cross-mating between SAMP8 and JF1 (Japanese Fancy Mouse 1) normal mice was performed for the genetic studies. At 5 months of age, learning and memory deficits (LMD) of F2 and backcross progenies were assessed using a Step-Through passive avoidance apparatus. The F2 generation showed a 3:1 segregation ratio of LMD to normal mice, and the backcross generation segregated into a 1:1 ratio of LMD to normal mice. These results are in good agreement with Mendelian inheritance. Estimation of the number of genes using Wright's formula showed that at least two to three genes are involved in the development of LMD in SAMP8 mice. Thus, LMD in SAMP8 mice may be inherited by a relatively small number of genes and regulated by a major single gene. In further experiments, we conducted QTL analysis to identify memory dysfunction QTLs in SAMP8 mice using 264 F2 progenies. A total of 126 genetic markers were typed in all chromosomes. Four significant QTLs to LMD were identified on chromosomes 1, 12, 13, and 15. The number of these QTLs is almost consistent with the statistically estimated gene number. Congenic strains carrying the QTLs need to be produced to verify the existence of LMD genes in the candidate regions of the chromosomes.

A new inbred strain JF1 established from Japanese fancy mouse carrying the classic piebald allele.

A new inbred strain JF1 (Japanese Fancy Mouse 1) was established from a strain of fancy mouse. Morphological and genetical analysis indicated that the mouse originated from the Japanese wild mouse, Mus musculus molossinus. JF1 has characteristic coat color, black spots on the white coat, with black eyes. The mutation appeared to be linked to an old mutation piebald (s). Characterization of the causative gene for piebald, endothelin receptor type B (ednrb), demonstrated that the allele in JF1 is same as that of classic piebald allele, suggesting an identical origin of these two mutants. Possibly, classic piebald mutation was introduced from the Japanese tame mouse, which was already reported at the end of the 1700s. We showed that JF1 is a useful strain for mapping of mutant genes on laboratory strains owing to a high level of polymorphisms in microsatellite markers between JF1 and laboratory strains. The clarified genotypes of JF1 for coat color are "aa BB CC DD ss".

The origin of common laboratory mice.

The house mouse is one of the model organisms in genetics and more than 400 inbred strains have been established. However, many of the strains are related and their ancestry can be traced back to European fancy mice inbred in the 1920s. Recent molecular studies corroborate the early historical records that assert that Japanese fancy mice were introduced into European stocks and thus contributed to the development of "old" inbred strains. Consequently, many inbred strains have genomic DNA derived from more than one subspecies of Mus musculus. The subspecific hybrid origin of common inbred strains has important bearings on the interpretation of genetic data, and the limitations that history imposes upon the currently available strains make it necessary to establish new inbred strains representing specific wild populations.

What mouse contributed the first representation of the adrenal cortex X zone?

The X zone, innermost cortex of the mouse adrenal, was first represented by Kiyoshi Masui and Yasushige Tamura in the Japanese in 1924 and in the English in 1926. All the mice used by them were reared by themselves at the Laboratory of Veterinary Anatomy, Faculty of Agriculture, Imperial University of Tokyo. They were the first scientists in Japan that attempted to breed mice in their own laboratory and used them for scientific researches in the literature. The importance of the breeding of laboratory animals by users was first pointed out by Sahachiro Hata in 1914, who found Salvarsan as a specific medicine against Spirochaeta pallida in cooperation with Paul Ehrlich in 1910. Hata's idea on the breeding of laboratory animals by researchers themselves might inspire Masui. Hata himself tried to breed laboratory mice in the Kitasato Institute. They were called "French mice", because they were believed at that time to be introduced from Europe before 1910. Masui and Seitaro Adachi (1926) also used French mice in their basic studies. They compared the body size between French and Nanking mice with special attention to the genetic factors controlling the body size for the purpose of improving of army horses. They noticed that French mice were larger in body size and more active in reproduction. Hata noticed a difference in reaction to Salvarsan between two mice. Our survey of the literature revealed that the X zone in the mice used by Masui and Tamura had many distinctive characteristics. The major two found in 90-day-old virgins were the extremely thick X zone and its division into two sublayers, one being composed of vacuolated cells only and the other of non-vacuolated cells only. It seems most reasonable to postulate that the first representation of the X zone was made in French mice bred by Masui and Tamura themselves. These characteristics of the X zone in the mice used by Hata or Masui and Tamura were very similar to those observed in inbred strains of mice, KK and NC, which Kyoji Kondo established from Japanese fancy mice, Kasukabe and Nishikinezumi groups, respectively. The same characteristics were also found in 4 of 28 recombinant inbred (RI) strains between A/J and SM/J established by Masahiko Nishimura. Since both A/J and SM/J have not such characteristics, the thick X zone consisting of 2 sublayers with and without vacuolation seems to appear on a certain specific genetic background.(ABSTRACT TRUNCATED AT 400 WORDS)

Genetic Polymorphism of Murine C3 Controlled by a Single Co-Dominant Locus on Chromosome 17

Abstract Genetic polymorphism of murine C3 was demonstrated by a combined use of isoelectric focusing (IEF) in thin layer polyacrylamide gel and immunofixation. All 18 inbred strains, which were originally derived from the United States, showed a single C3 band of pI 6.1. In contrast, two strains (NC and NBr) derived from the Japanese fancy mouse and a strain (MoA), which was established from Japanese wild mouse (Mus musculus molossinus), showed a single but more anodal C3 band of pI 6.0. A mixture of plasma from two different strains, one from the Japanese mouse and another from the mouse of American origin, resulted in two discrete C3 bands; neither of these two bands can be distinguished from the C3 band observed in one of the unmixed plasmas. Breeding experiments established that the pI variation of mouse C3 is inherited as an autosomal co-dominant trait controlled by a single locus. Thus, the C3 gene segregated in the classical Mendelian ratio among second generation progeny from a cross between NC and one of the American strains, B10, BALB/c, or CBA. The locus controlling the pI variation of murine C3 was designated as C3-1 locus and its linkage with other genetic markers was studied. The C3-1 locus segregated relative to Albino, Agouti, Brown, Es-1, HC, and Id-1. However, the linkage of the C3-1 locus to two loci, Ce-2 and the S region of the H-2 complex was observed. Both of these two loci are localized to chromosome 17. The distances of the C3-1 locus from Ce-2 and S were estimated as 23 and 11 centimorgans, respectively. These values imply that the C3-1 locus is located outside H-2 of the chromosome 17.

近交系マウスにおける生化学的標識遺伝子の重要性

In order to check genetic purity of inbred strains of mice, we surveyed five biochemical variants in certain 69 strains, some of which had established from Japanese fancy mice. The loci examined were Hemoglobin beta-chain, Malic enzyme (supernatant form), Isocitrate dehydrogenase (supernatant form), Serum esterase-1, and Serum esterase-2. These loci were all in homozygous states as far as examined, however some subline divergences were found in a few strains, that is to say, sublines were found to be fixed with different alleles as some loci, Important of biochemical marker genes to check genetic purity of strains and several derived problems are mentioned.