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Background: The "four core genotypes" (FCG) mouse model has emerged as a major model testing if sex differences in phenotypes are caused by sex chromosome complement (XX vs. XY) or gonadal hormones or both. The model involves deletion of the testis-determining gene Sry from the Y chromosome and insertion of an Sry transgene onto an autosome. It produces XX and XY mice with testes, and XX and XY mice with ovaries, so that XX and XY mice with the same type of gonad can be compared to assess phenotypic effects of sex chromosome complement in cells and tissues. Findings: We used PCR to amplify the Sry transgene and adjacent genomic sequences, to resolve the location of the Sry transgene to chromosome 3 and confirmed this location by fluorescence in situ hybridization (FISH) of the Sry construct to metaphase chromosomes. Using quantitative PCR, we estimate that 12-14 copies of the transgene were inserted. The anogenital distance (AGD) of FCG pups at 27-29 days after birth was not different in XX vs. XY males, or XX vs. XY females, suggesting that differences between XX and XY mice with the same type of gonad are not caused by difference in prenatal androgen levels. Conclusion: The Sry transgene in FCG mice is present in multiple copies at one locus on chromosome 3, which does not interrupt known genes. XX and XY mice with the same type of gonad do not show evidence of different androgen levels prenatally. [ABSTRACT FROM AUTHOR]

The proper functioning of the placenta requires specific patterns of methylation and the appropriate regulation of retroelements, some of which have been co-opted by the genome for placental-specific gene expression. Our inquiry was initiated to determine the causes of the placental defects observed in crosses between two species of mouse, Mus musculus and Mus caroli. M. musculus × M. caroli fetuses are rarely carried to term, possibly as a result of genomic incompatibility in the placenta. Taking into account that placental dysplasia is observed in Peromyscus and other Mus hybrids, and that endogenous retroviruses are expressed in the placental transcriptome, we hypothesized that these placental defects could result, in part, from failure of the genome defense mechanism, DNA methylation, to regulate the expression of retroelements. Hybrid M. musculus × M. caroli embryos were produced by artificial insemination, and dysplastic placentas were subjected to microarray and methylation screens. Aberrant overexpression of an X-linked Mus retroelement in these hybrid placentas is consistent with local demethylation of this retroelement, concomitant with genome instability, disruption of gene regulatory pathways, and dysgenesis. We propose that the placenta is a specific site of control that is disrupted by demethylation and retroelement activation in interspecific hybridization that occur as a result of species incompatibility of methylation machinery. To our knowledge, the present data provide the first report of retroelement activation linked to decreased methylation in a eutherian hybrid system.