2001 Fiscal Year Final Research Report Summary
Molecular mechanism of sex determination and its disease
| Project/Area Number |
11670168
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SEMBA Kentaro The Institute of Medical Science, The University of Tokyo, Dept. of Cancer Biology, Div. of Cellular and Molecular Biology, Associate professor, 医科学研究所, 助教授 (70206663)
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| Project Period (FY) |
1999 – 2000
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| Keywords | sex / WT1 / SRY |
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| Research Abstract |
In humans, as in other mammals, sex determination is controlled by a dominant switch termed TDF for Testis Determining Factor. The SRY gene is thought to be the TDF, which encodes a transcription factor with one HMG box as a DNA binding domain. Mutations in the SRY HMG box have been identified in 15% cases of XY sex reversal in humans. Introduction of mouse SRY gene (Sry) into XX female mice induced testis differentiation and subsequent male development. However, little is known about mechanism of transcriptional regulation by SRY. WT1 mutations have frequently been observed in Denys-Drash syndrome (DDS) patients with urogenital malformation.
During analysis of WT1-associated proteins, we found that WT1 bound to Sox30, which encodes a novel transcription factor with one HMG box. Further analysis showed that WT1 bound to its HMG box. This observation prompted us to analyze interaction between WT1 and SRY, both of which are expressed in the somatic cells of early gonads. We showed the following results:
i) WT1 binds to SRY in vitro and in cultured cells.
ii) WT1 and SRY synergistically activate transcription from a promoter that contains SRY binding sequence and also from the SRY promoter.
iii) WT1 mutants found in DDS, however, did not show this activity.
iv) WT1 is recruited on a SRY-binding sequence in a SRY-dependent manner, while recruitment of DDS mutants is significantly reduced.
These observations suggest that WT1 and SRY interaction plays an important role in early gonadal development and its disease. Recently we have established cell lines which express both WT1 and SRY. We are currently analyzing the expression profile of this cell line, which will reveal target genes regulated by WT1 and SRY.
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Research Products
(4 results)
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[Publications] Osaki, E., Nishina, Y, Inazawa, J., Copeland, N.G., Gilbert, D. J., Jenkins, N. A., Ohsugi, M., Tezuka, T., Yoshida, M., and Semba, K.: "Identification of a novel Sry-related gene and its germ cell-specific expression."Nucleic Acids Res. 27. 2503-10 (1999)
Description
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