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Foxl2 Up-Regulates Aromatase Gene Transcription in a Female-Specific Manner by Binding to the Promoter as Well as Interacting with Ad4 Binding Protein/Steroidogenic Factor 1

Laboratory of Reproductive Biology (D.-S.W., T.K., L.-Y.Z., B.P.-P., S.I., F.S., K.O., Y.N.), National Institute for Basic Biology, Okazaki 444-8585, Japan; Solution-Oriented Research for Science and Technology (D.-S.W., S.I., F.S., K.O., K.-i.M., Y.N.), Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan; Department of Molecular Biomechanics (L.-Y.Z., Y.N.), Graduate University for Advanced Studies, Okazaki 444-8585, Japan; School of Life Science (D.-S.W.), Southwest University, 400715 Chongqing, P.R. China; National Research Institute of Aquaculture (T.K.), Tamaki, Mie 516-0423, Japan; and Laboratory of Sex Differentiation (K.-i.M.) National Institute for Basic Biology, Okazaki 444-8585, Japan

Address all correspondence and requests for reprints to: Professor Yoshitaka Nagahama, Laboratory of Reproductive Biology, Department of Developmental Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan. E-mail: nagahama{at}nibb.ac.jp.

Increasing evidence suggests the crucial role of estrogen in ovarian differentiation of nonmammalian vertebrates including fish. The present study has investigated the plausible role of Foxl2 in ovarian differentiation through transcriptional regulation of aromatase gene, using monosex fry of tilapia. Foxl2 expression is sexually dimorphic, like Cyp19a1, colocalizing with Cyp19a1 and Ad4BP/SF-1 in the stromal cells and interstitial cells in gonads of normal XX and sex-reversed XY fish, before the occurrence of morphological sex differentiation. Under in vitro conditions, Foxl2 binds to the sequence ACAAATA in the promoter region of the Cyp19a1 gene directly through its forkhead domain and activates the transcription of Cyp19a1 with its C terminus. Foxl2 can also interact through the forkhead domain with the ligand-binding domain of Ad4BP/SF-1 to form a heterodimer and enhance the Ad4BP/SF-1 mediated Cyp19a1 transcription. Disruption of endogenous Foxl2 in XX tilapia by overexpression of its dominant negative mutant (M3) induces varying degrees of testicular development with occasional sex reversal from ovary to testis. Such fish display reduced expression of Cyp19a1 as well as a drop in the serum levels of 17ß-estradiol and 11-ketotestosterone. Although the XY fish with wild-type tilapia Foxl2 (tFoxl2) overexpression never exhibited a complete sex reversal, there were significant structural changes, such as tissue degeneration, somatic cell proliferation, and induction of aromatase, with increased serum levels of 17ß-estradiol and 11-ketotestosterone. Altogether, these results suggest that Foxl2 plays a decisive role in the ovarian differentiation of the Nile tilapia by regulating aromatase expression and possibly the entire steroidogenic pathway.

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