EXCEED THE SPACE PROVIDED. The long-term goal of this research project is to identify genes involved in gonadal sex determination (GSD). Normally XX human beings develop as females with two ovaries and XY individuals develop as males with two testes. Exceptions occur, however, and not all are explained. For example, children are identified with a sex chromosome compliment that does not agree with their gonadal development. In some XX males, the Y-linked testis determining gene, SRY, is present, but in other cases no Y chromosome sequences are detected. Similarly, in some XY females the SRY gene is absent or abnormal, but in other cases an intact SRY gene is present. Despite the obvious clinical importance of these sex reversal (SR) cases, our understanding of the molecular control of sex determination remains rudimentary. With the cloning of Sry came the expectation that all GSD genes would be identified rapidly and this would reveal a simple pathway leading to ovarian and testicular development. However, the emerging picture is that the GSD pathway involves a complex network of interacting genes rather than a simple linear pathway. There has been progress and some additional GSD genes have been identified, but the complete set is not known. This project will utilize the mouse as a model to identify new GSD genes and to test the hypothesis that transcription factors involved in urogenital ridge formation and early gonad development are dosage sensitive. All available information indicates that the genes involved in determining whether ovarian or testicular tissue develops are the same in human beings and mice. Thus, the information gained from the proposed studies will lead directly to identifying human GSD genes. Five inherited XY SR conditions will be investigated with the goal of positionally cloning two new GSD genes, fine mapping a third GSD gene in preparation for positional cloning, and genetically mapping several additional new GSD genes. Genetic mapping will be accomplished using backcross and deletion mapping methods. Targeted mutations in GSD candidate genes will be produced in ES cells. ES cell-derived mice will be recovered and tested to determine if the mutation affects gonad development. PERFORMANCE SITE ========================================Section End===========================================
| 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 |
| Bergstrom, David E; Bergstrom, Rebecca A; Munroe, Robert J et al. (2003) Overlapping deletions spanning the proximal two-thirds of the mouse t complex. Mamm Genome 14:817-29 |
