The long-term objective of this project is to use the mouse as an experimental tool to investigate the genetic control of mammalian primary (gonadal) sex determination by identifying and determining the mode of action of genes that cause inappropriate gonadal development in XX and XY individuals. These results may help explain clinical cases among human beings in which XX individuals that lack Y chromosomal DNA sequences develop testicular tissue and XY individuals that contain an intact Y-linked testis determining (TDF) gene develop ovarian tissue.
The specific aims i n this proposal are to: I. Identify autosomal loci that cause ovarian tissue development in C57BL/6J mice that carry specific Mus domesticus Y chromosomes, map each locus to a 10 centimorgan (cM) chromosomal segment, and map a subset of these loci to a 1 cM segment. II. Identity the genetic basis for delayed testicular cord formation in C57BL/6J XY mice inheriting certain Mus domesticus Y chromosomes. III. Identify the critical site(s) in the Y-linked testis determining (Tdy) gene from Mus domesticus poschiavinus that causes ovarian tissue development when present in C57BL/6J mice. Methodologies include construction of genetic crosses, linkage analysis, deletion mapping, histology, transgenic mouse construction, and molecular techniques (e.g., DNA isolation, Southern blotting, PCR, DNA sequencing, DNA subcloning, library construction, site-directed mutagenesis).
| Correa, Stephanie M; Washburn, Linda L; Kahlon, Ravi S et al. (2012) Sex reversal in C57BL/6J XY mice caused by increased expression of ovarian genes and insufficient activation of the testis determining pathway. PLoS Genet 8:e1002569 |
| Bouma, Gerrit J; Hudson, Quanah J; Washburn, Linda L et al. (2010) New candidate genes identified for controlling mouse gonadal sex determination and the early stages of granulosa and Sertoli cell differentiation. Biol Reprod 82:380-9 |
| Wilhelm, Dagmar; Washburn, Linda L; Truong, Vy et al. (2009) Antagonism of the testis- and ovary-determining pathways during ovotestis development in mice. Mech Dev 126:324-36 |
