The development of the male gonad is dependent on the function of the sex determining locus (Sry) present on the Y chromosome. It is generally believed that Sry initiates a cascade of gene interactions that transforms an undifferentiated gonad into a testis. In some instances testis differentiation fails even in the presence of a Y chromosome. This """"""""sex reversal"""""""" is present in the human population causing the development of sterile XY females with high incidence of gonadoblastoma and /or malignant germ cell tumors. Understanding the genesis of this phenotype is therefore an important health issue. These studies will also provide an insight into the mechanisms of gonadal development. This proposal addresses the role of Sry in development of the male gonad using the sex reversal XYDO mouse model. In the XYDOM sex reversal, the Y chromosomes of the M. domesticus vary in their ability to induce testes in the strain C57Bl/6. To elucidate the molecular basis of XYDOM sex reversal the P.I. proposes experiments along the following specific aims: 1. Quantify the Sry expression during testis differentiation in XYDOM sex reversed strains to determine if sex reversal results from a delay in initiation and/or suboptimal expression of Sry. 2. Determine if suboptimal Sry mRNA translation contributes to XYDOM sex reversal. 3. Characterize the molecular mechanism by which the oncogene Kit exacerbates XYDOM sex reversal. 4. Characterize the inter-relationship of Mullerian inhibiting substance and XYDOM sex reversal. 5. Generate and characterize immortalized fetal gonadal cell lines and XYSxr embryonic germ cells to complement XYDOM sex reversal studies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Reproductive Biology Study Section (REB)
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Tasca, Richard J
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Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Nagamine, C M; Morohashi, K; Carlisle, C et al. (1999) Sex reversal caused by Mus musculus domesticus Y chromosomes linked to variant expression of the testis-determining gene Sry. Dev Biol 216:182-94
Nagamine, C M; Capehart, J; Carlisle, C et al. (1998) Ovotestes in B6-XXSxr sex-reversed mice. Dev Biol 196:24-32
Nagamine, C M; Carlisle, C (1997) Zfy2/1 fusion gene fails to replicate Zfy1 expression pattern in fetal gonads. Genomics 43:397-8
Carlisle, C; Winking, H; Weichenhan, D et al. (1996) Absence of correlation between Sry polymorphisms and XY sex reversal caused by the M. m. domesticus Y chromosome. Genomics 33:32-45
Nagamine, C M; Carlisle, C (1996) The dominant white spotting oncogene allele Kit(W-42J) exacerbates XY(DOM) sex reversal. Development 122:3597-605
Nagamine, C M (1994) The testis-determining gene, SRY, exists in multiple copies in Old World rodents. Genet Res 64:151-9
Nagamine, C M; Shiroishi, T; Miyashita, N et al. (1994) Distribution of the molossinus allele of Sry, the testis-determining gene, in wild mice. Mol Biol Evol 11:864-74