The rat will be used as a model system to address a fundamental question of growth control. The particular case investigated here is control of pituitary growth in the presence of estrogen and is relevant to estrogen's role in tumor formation and reproductive biology. Chronic treatment with estrogen induces pituitary tumors in the rat strain Fischer 344 while other strains, such as Holtzman or Brown Norway, are resistant to this induction. Previous genetic analysis suggested that the effect is due to variation at two or three genetic loci. To investigate the mechanism by which this growth control occurs, or fails to occur, the genes responsible will be mapped, cloned, and analyzed. Fischer 344 and a tumor resistant strain, Brown Norway, will be crossed and their progeny intercrossed to produce an F2 population. The F2 animals will be tested for estrogen induction of pituitary tumors and the quantitative trait of estrogen-induced tumor mass will be mapped using simple sequence repeats as genetic markers and the interval mapping program MAPMAKER QTL. This data will also be used to measure the magnitude of effect of each mapped locus and the dominance or additivity relationship between alleles at each locus. The relevant genes will then be isolated for sequence analysis by positional cloning. The genomic subtractive hybridization technique known as genetically directed representational difference analysis will be employed to isolate DNA sequence polymorphisms in the genes at the mapped loci. These polymorphisms will be used as molecular tags to clone the actual genes involved in induction of pituitary tumor.
| Wendell, D L; Gorski, J (1997) Quantitative trait loci for estrogen-dependent pituitary tumor growth in the rat. Mamm Genome 8:823-9 |
