International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 146 - GENETIC PATHWAY ANALYSIS OF MOM1 CANDIDATE GENES

Cormier R, McAlpine C, Bogan C, Bluemn E

University of Minnesota School of Medicine, Duluth, MN, United States

The Multiple Intestinal Neoplasia (Min) mouse has been extensively studied as a model for the human form of colorectal cancer called familial adenomatous polyposis (FAP).  Min mice carry a germline heterozygous mutation in the Apc gene that predisposes to the development  of numerous adenomas throughout the intestinal tract. Notably, the Min phenotype is mouse strain dependent.  For example, the C57BL/6 strain is highly sensitive to Min-induced intestinal tumorigenesis, while several strains, including AKR, are highly resistant to tumor development.  Linkage analysis of backcross progeny arising from crosses between tumor resistant and sensitive strains has mapped a major resistance modifier of the Min phenotype to distal chromosome four. This tumor resistance locus, called Mom1 (Modifier of Min 1), has been shown to consist of a complex of two or more closely linked candidate genes.  Our laboratory has a major research focus in the identification and functional characterization of the Mom1 genes.  We continue work conducted over a number of years by groups in Madison, WI and Cambridge, MA. These collaborative studies indicate that the proximal Mom1 gene is likely to be Pla2g2a, which encodes for a phospholipase that is active at the plasma membrane. Pla2g2a provides resistance to Min tumorigenesis throughout the intestine but especially in the colon.  In contrast the distal Mom1 component exerts a resistance phenotype that is restricted to the small intestine.  Ongoing experiments include efforts to map and clone the distal Mom1 gene.  Progress on this mapping project will be presented.  In addition, we intend to present results of a functional test of a distal Mom1 candidate gene that carries a targeted knockout mutation that has been introgressed into the C57BL/6-Min strain.  To understand the action of the proximal Mom1 gene, Pla2g2a, we have experiments underway to identify genetic pathways utilized by Pla2g2a.  These include potential interactions with PPARg and Mucin 2.

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