Genetic mapping of Mom5, a novel modifier of Apc(Min)-induced intestinal tumorigenesis.
The initial purpose of this study was to assess the role of estrogen receptor beta (ERbeta) in intestinal tumorigenesis by examining the effects of an ERbeta knockout (ERbeta(-/-)) on Apc(Min) mice. In order to accomplish this goal on a uniform genetic background, we were required to backcross the ERbeta knockout from the 129P2 genetic background to the B6 genetic background for 10 generations. Midway through this process, we performed a test cross in which mice from the N(5) backcross generation of the ERbeta knockout strain were intercrossed with Apc(Min/+) mice to obtain Apc(Min/+) ERbeta(+/+), Apc(Min/+) ERbeta(+/-) and Apc(Min/+) ERbeta(-/-) mice. Intestinal tumorigenesis in the N(5)F(2) mice was evaluated at 14 weeks of age. The analysis of the impact of ERbeta in the N(5) cross was complicated by segregating 129P2-derived alleles that affected tumor number and were unlinked to ERbeta. Genetic linkage analysis of this cross permitted the localization of a single genetic modifier of tumor number in Apc(Min/+) mice. This locus, Modifier of Min 5 (Mom5), maps to proximal mouse chromosome 5; the 129P2 allele of this locus is associated with a 50% reduction in mean intestinal tumor number. Through in silico analysis and confirmatory sequencing, we have identified the Rad50-interacting protein-1 gene as a strong candidate for Mom5.
Oikarinen
Seija I
SI
Department of Applied Chemistry and Microbiology (Nutrition), University of Helsinki, PO Box 66, Helsinki FIN-00014, Finland.
Cleveland
Alicia G
AG
Cork
Karlene M
KM
Bynoté
Kimberly K
KK
Rafter
Joseph J
JJ
Gustafsson
Jan-Ake
JA
Mutanen
Marja
M
Gould
Karen A
KA
D000236:Adenoma / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D047629:Estrogen Receptor beta / Q000235:genetics / Q000502:physiology*; D005095:Exoribonucleases; D005260:Female; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data
D002352:Carrier Proteins; D047629:Estrogen Receptor beta; D005095:Exoribonucleases; C443126:Prnpip1protein, mouse