International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


Dr Revati Koratkar
Thomas Jefferson University
Dept of Immunology, Rm # 719, Kimmel Cancer Canter
233 South 10th Street
Philadelphia, PA 19107

Co-Authors: Buchburg, A.M., and Siracusa, L.
Institutions: Thomas Jefferson University

The Multiple Intestinal neoplasia (Min) mouse is an extensively studied model closely resembling most genotypic and phenotypic features presented in Familial Adenomatous Patients.  Intestinal adenoma development in ApcMin/+ mice is strongly influenced by genetic background.  A major modifier of polyp multiplicity has been localized to the distal end of mouse chromosome 4, called Modifier of Min 1 (Mom1).  Among the various strains analyzed for polyp multiplicity, CAST/Ei x B6 ApcMin/+ F1 offspring had the least number of polyps (10.5 + 4.5), compared to B6 ApcMin/+ mice (59.9 + 25.5). The Mom1 locus accounts for ~50% of genetic variability found in ApcMin/+ mice, thus suggesting that the CAST strain carries additional modifiers.  To test this hypothesis, we generated a congenic line between the CAST and B6 inbred strain to study the effects of a resistant CAST background in the absence of a known modifier (Mom1R) allele.  The CAST strain was selected not only because of the low polyp numbers observed in the CAST/Ei x B6 ApcMin/+ F1 hybrids, but also because CAST mice have diverged from common inbred laboratory strains by 1-2 million years.  Because of divergent evolution, the CAST strain should contain unique alleles of many genes, thus providing a rich genetic reservoir for identification of new modifier genes.

Female mice from the CAST.B6 Mom1R/S congenic line were mated with B6 ApcMin/+ male mice.  The F1 hybrid offspring were genotyped to determine their allelic status at both Apc and Mom1 loci.  Progeny carrying the ApcMin/+ mutation were aged to 100 and 200 days, then screened for intestinal tumor phenotypes.  There was a significant decrease (p < 0.001) in polyp multiplicity in the CAST.B6 Mom1R/SApcMin/+ F1 offspring compared to B6 ApcMin/+ mice at both 100 and 200 days.  Similarly, a significant decrease (p < 0.001) was observed in polyp numbers in the CAST.B6 Mom1S/SApcMin/+ F1 offspring compared to the B6 ApcMin/+ mice at 100 and 200 days.  Comparing the F1 hybrid offspring, a significant increase in polyp numbers was observed at 100 versus 200 days within each class of offspring Mom1R/S  (p < 0.01) and Mom1S/S (p < 0.01). A complete absence of colon tumors in all mice carrying the CAST background was observed.

These results indicate that the resistant cast/ei strain carries additional modifiers, unlinked to mom1 that effectively reduce tumor burden in the small and large intestines of apcmin/+ mice.

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