129S1/SvImJ-Chr 19^MOLF/Ei/NadJaheJ

Stock number: 029319
Product name: 129.MOLF-Chr19 consomic (or M19)
Strain synonyms: CSSM19, CSS-M19, M19
Research areas: Cancer Research, Reproductive Biology Research, Research Tools

Description

Homosomic males from the chromosome 19 consomic strain 129S1/SvImJ-Chr19^MOLF/Ei/NadJahe (also called 129.MOLF-Chr19 or M19) exhibit ~75% spontaneous testicular germ cell tumors (TGCTs). These mice are useful for studying susceptibility to TGCT - the most common solid tumors in human males aged 15–34.
This strain represents one of a panel of inter-species chromosome substitution (or consomic) strains. Each strain carries a chromosome from the Mus musculus molossinus wild-derived strain MOLF/Ei introgressed into a Mus musculus domesticus 129S1/SvImJ background. These strains provide a tool for dissection of quantitative trait loci.

Detailed description

The chromosome 19 consomic strain 129S1/SvImJ-Chr19^MOLF/Ei/NadJahe (also called 129.MOLF-Chr19 or M19) represents one of a panel of inter-species chromosome substitution (or consomic) strains. Each strain carries a chromosome from the Mus musculus molossinus wild-derived strain MOLF/Ei introgressed into a Mus musculus domesticus 129S1/SvImJ background. The MOLF strain is separated from the common inbred strain progenitors by approximately 100,000 years. These strains represent a tool for dissection of quantitative trait loci.

The M19 mice are useful for studying genetic susceptibility to testicular germ cell tumors (TGCTs) - the most common solid tumors in human males aged 15–34. Homosomic and heterozygous M19 males have a spontaneous TGCT rate of ~75% and ~25%, respectively, whereas the incidence ~5% in 129S1/SvImJ males. Spontaneous TGCTs have not been observed in MOLF/Ei. For homosomic M19 males, unilateral and bilateral primary tumors are observed, and putative metastases have been reported. M19 males are fertile, but may exhibit some breeding difficulties if large tumors are present (details below). For homosomic M19 females, there is no evidence for reduced fertility (no germ cell defects have been detected).


Whereas 129 mice homozygous for the Dnd1^Ter mutation (129T1/Sv-Oca2⁺ Tyr^c-ch Dnd1^Ter/J ; Stock No. 000091) have a TGCT incidence of ~90% and are also deficient for normal germ cells, these homosomic M19 males show most germ cells develop normally. Thus, both normal and transformed germ cells are present in the M19 testis, and M19 males can be fertile despite having testicular tumors.


In M19 males, the window of TGCT initiation is during embryogenesis (embryonic day (E)12.5-15.5). ~75% of M19 males develop tumors in utero and that incidence does not increase with age. At E15.5, the tumor stem cells (pluripotent embryonal carcinoma [EC] cells) first appear and form foci of cells. By E18.5, the EC cells have started to differentiate into cell types derived from all three embryonic germ layers (teratoma). Histologically, various stages of tumor progression are visible from ~E15.5 onward. The donating investigator reports that gross visual observation of testicular tumors is reliable by 6-8 weeks of age. Tumors grow for a while after birth, but because they ultimately form mature teratomas (i.e., contain fully differentiated cell types), the cells eventually become quiescent and the tumor stops growing (or may even regress). Tumor size is random: some adult males exhibit very large tumors - but this has no correlation with advancing age.


Multiple TGCT susceptible loci have been mapped to chromosome 19 of the M19 strain. These loci either act independently or interact epistatically to contribute to testicular tumor development. Susceptibility genes/variants exist in both the donor (MOLF/Ei) and host (129S1/SvImJ) genome. Several publications examine M19 testicular germ cell tumor quantitative trait loci and/or specific genes (Youngren et al. 2003 Hum Mol Genet 12:389, Zhu et al. 2007 Mamm Genome 18:584 and Zhu et al. 2010 Cancer Res 70:7264).

Development

The laboratory of Dr. Joseph Nadeau (Case Western Reserve University) developed the 129S1/SvImJ-Chr #^MOLF/Ei/Nad strain set by replacing individual chromosomes from the MOLF/Ei donor strain into the 129S1/SvImJ host strain using a marker-assisted series of backcrosses.
Using this approach, the chromosome 19 consomic strain 129S1/SvImJ-Chr19^MOLF/Ei/NadJahe (also called 129.MOLF-Chr19 or M19) was created by Dr. Angabin Matin while in the laboratory of Dr. Nadeau. At backcross generations three and four, females with non-recombinant MOLF/Ei-derived chromosome 19 were crossed with 129S1/SvImJ males - thus the Y chromosome of the consomic strain is of 129S1/SvImJ origin. After working with the M19 mice in Dr. Nadeau's lab, Dr. Jason D. Heaney transferred the mice to Baylor College of Medicine in 2012. From there, homosomic mice (both females and males) with agouti coat color were sent to The Jackson Laboratory in 2017.

From 2017-2021, a 135 SNP panel (distinguishing between 129S1/SvImJ and MOLF/EiJ markers) was performed on the mice sent to The Jackson Laboratory (and on the mice recovered from the cryopreserved embryos). These analyses showed, as expected, that all 10 SNPs on Chromosome 19 were homozygous for MOLF/EiJ allele-type. In addition, this revealed a region of Chromosome 1 homozygous for MOLF/EiJ allele-type: the most proximal Chromosome 1 SNP [~7.2 Mb] was homozygous for MOLF/EiJ allele-type, while the next closest Chromosome 1 SNP [~46.0 Mb] was homozygous 129S1/SvImJ allele-type.