International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


H. W Wang
Baylor College of Medicine

1) Hongmei W, 2) Laura S, 2) Ken M  1) Colin E B
1) Baylor College of Medicine 2) Institut Pasteur, Paris, France

Mutations in SRY are responsible for many human cases of 46, XY females, and most cases of XX sex reversal are due to the presence of cryptic fragments of the Y carrying SRY. However, XY (Sry+) females and XX(Y-) males are not uncommon and are assumed to be due to mutations in SRY interacting proteins or downstream pathway genes. At present, the exact mechanism of SRY action is unknown. In order to address this gap in our understanding of sex determination, we have been searching for SRY interacting proteins. We screened a human testis expression library with recombinant SRY protein and positive clones were subsequently detected with a specific anti-SRY antibody. A candidate SRY interacting gene, TGIF (nuclear transcriptional corepressor TG-interacting factor) was identified and is a member of the TALE homeodomain protein family involved in transcription repression. In situ hybridization and immunohistochemistry data showed that human SRY and TGIF co-express in the developing fetal testis at the time of sex determination. Co-immunoprecipitation and far western analysis were used to verify the interaction. In addition, the mammalian two-hybrid system was used to confirm the interaction in vivo using human and mouse SRY/Sry and TGIF/Tgif constructs. We also show, using cell culture techniques, that the interaction of SRY with TGIF could de-repress the transcription repression effect of TGIF in human and mouse. We propose a model of sex determination in which SRY negatively regulates the repressor activity of TGIF thereby permitting the expression of male-determining genes.

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