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The Proximal Gata4 Promoter Directs Reporter Gene Expression to Sertoli Cells During Mouse Gonadal Development¹

Ontogeny-Reproduction Research Unit,⁵ Centre de Recherche du Centre Hospitalier Universitaire de Québec, Centre de Recherche en Biologie de la Reproduction, Department of Obstetrics and Gynecology, Laval University, Québec City, Québec, Canada G1K 7P4 Faculty of Veterinary Medicine,⁶ University of Montreal, St-Hyacinthe, Québec, Canada J2S 7C6

ABSTRACT

The GATA4 transcription factor is an important developmental determinant for many organs, such as the heart, gut, and testis. Despite this pivotal role, our understanding of the transcriptional mechanisms that control the proper spatiotemporal expression of the GATA4 gene remains limited. We have generated transgenic mice expressing a green fluorescent protein (GFP) marker under the control of rat Gata4 5' flanking sequences. Several GATA4-expressing organs displayed GFP fluorescence, including the heart, intestine, and pancreas. In the gonads, while GATA4 is expressed in pregranulosa, granulosa, and theca ovarian cells, and Sertoli, Leydig, and peritubular testicular cells, the first 5 kb of Gata4 regulatory sequences immediately upstream of exon 1 were sufficient to direct GFP reporter expression only in testis and, specifically, in Sertoli cells. Onset of GFP expression occurred after Sertoli cell commitment and was maintained in these cells throughout development to adulthood. In vitro studies revealed that the first 118 bp of the Gata4 promoter is sufficient for full basal activity in several GATA4-expressing cell lines. Promoter mutagenesis and DNA-binding experiments identified two GC-box motifs and, particularly, one E-box element within this –118-bp region that are crucial for its activity. Further analysis revealed that members of the USF family of transcription factors, especially USF2, bind to and activate the Gata4 promoter via this critical E-box motif.

developmental biology, gene regulation, Sertoli cells, testis

⁴These authors contributed equally to this work.

¹Supported by grants from the Canadian Institutes of Health Research (CIHR) to D.W.S. and R.S.V. R.S.V. is the titleholder of the Canada Research Chair in Reproduction and Sex Development. S.M.G. holds a postdoctoral fellowship from the CIHR Institute of Gender and Health. A.T. was recipient of a studentship from la Chaire Jeanne et Jean-Louis Lévesque.

Correspondence: ² Robert S. Viger, Ontogeny-Reproduction Research Unit, CHUL Research Centre (CHUQ), Room T1–49, 2705 Laurier Blvd., Québec City, QC, Canada G1V 4G2. FAX: 418 654 2765; e-mail: robert.viger{at}crchul.ulaval.ca

Correspondence: ³ David W. Silversides, Faculty of Veterinary Medicine, University of Montreal, 3200 Sicotte, CP 5000, St-Hyacinthe, QC, Canada J2S 7C6. FAX: 450 778 8103; e-mail: david.w.silversides{at}umontreal.ca