In an inbred strain mouse model, two distinct loci have been mapped on Chr X (Gct4, Gct6) that have a deleterious effect on ovarian development leading to an increased probability of ovarian granulosa cell (GC) tumors. In genetically susceptible female mice, GC tumor development is restricted to the peri-pubertal period, indicating that tumor development is a defect of early ovarian maturation. The modifier effect of Gct4 and Gct6 on GC tumor frequency is governed by a gene-gene interaction and a paternal parent-of-origin effect, suggesting that both genetic and epigenetic mechanisms are significant for ovarian tumorigenesis. The objectives of this research proposal are two-fold: 1) to positionally clone the Gct4 gene using GC tumor frequency as a convenient phenotypic marker, and 2) to establish whether the Gct4 or Gct6 gene products show imprinted expression patterns in the ovary, as an explanation for their paternal, parent-of-origin-restricted support for GC tumor development. To positionally clone the Gct4 locus, a recombination mapping scheme is proposed that takes advantage of available congenic mouse sublines to provide both high genetic resolution and allelic variants of Gct4 as phenotypic discriminators. Gct4 candidate genes resolved by recombination mapping will be sequenced in the coding and regulatory regions to identify sequence variations that associate with Gct4 allelic variation for tumor susceptibility. Two experimental models are proposed for investigation of the imprinted nature of Gct4 and Gct6 genes. The first model utilizes available congenic mouse strains for allele-specific quantitative gene expression. The second model utilizes X-linked green fluorescent protein (GFP) transgenic strains to isolate ovarian GCs that actively transcribe from the maternal Chr X or paternal Chr X prior to a quantitative assay for Gct4 and Gct6 gene expression. ? Relevance of the Research to Public Health: The SWR mouse model for spontaneous ovarian granulosa cell (GC) tumor susceptibility provides a genetically defined animal model which closely resembles juvenile-onset GC tumors that develop in infants and young girls. The causes of this pediatric cancer are presently unknown; thus, identification of the high impact tumor susceptibility genes, the relevant gene interactions and patterns of inheritance that promote GC tumor development in the mouse will provide specific information for further investigation in human cases. Because genes on Chromosome X are well conserved in many mammalian species, it is even more likely that the X-linked Gct4 and Gct6 GC tumor susceptibility genes identified in this mouse model will have genetic counterparts on human Chromosome X. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD049397-02
Application #
7229980
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
2006-05-01
Project End
2007-08-31
Budget Start
2007-05-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$93,563
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609