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Submitted on July 28, 2003
Accepted on December 18, 2003
Gene during Villous Trophoblast Differentiation
Department of Obstetrics and Gynecology (M.K., L.S., S.B., P.H., H.H.), University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria; Institute of Medical Biochemistry (B.G., H.R.), University of Vienna, Dr. Bohr-gasse 9, A-1030 Vienna, Austria
* To whom correspondence should be addressed. E-mail: martin.knoefler{at}akh-wien.ac.at.
Expression of the trophoblast-specific subunit of human chorionic gonadotrophin, CG
, is associated with fusion of cytotrophoblasts into a multinuclear syncytium. Here, we studied regulation of the CG5 gene in trophoblasts undergoing in vitro syncytialisation. Transfection of luciferase reporters harboring different lengths of the CG5 upstream sequence revealed that the proximal promoter region (-345 + 114) is sufficient to govern differentiation-dependent induction. Mutational analyses suggested that two Sp and three AP-2 recognition sequences are necessary for full activity of the promoter. During syncytialisation these elements interacted with increasing amounts of the transcription factors Sp1, Sp3 and AP-2
in EMSA, but only AP-2 binding rose upon elevation of cAMP levels with forskolin. Increasing expression of different isoforms of Sp1 and Sp3 could also be detected by Western blot analyses. Sp1/Sp3 localized to syncytial nuclei both in differentiated cultures and in term placental tissue suggesting assembly of functional transcriptional complexes. Co-staining of the transcription factors with E-cadherin on term placental sections revealed that 47% and 33% of cytotrophoblast nuclei were negative for Sp1 and Sp3, respectively. In contrast, immunohistochemistry of early tissue demonstrated expression of Sp1 in the majority of cyto- and syncytiotrophoblasts whereas Sp3 was absent from the syncytium. Sp1 and Sp3 induced wild-type/mutant promoter constructs upon transfection in Sp-deficient SL-2 cells indicating that the Sp elements function as activating sequences. The data suggest that increasing concentrations of Sp1, Sp3 and AP-2 enhance transcription of CG in differentiating term trophoblasts, while a different combination of factors may control expression in early placentas.
5 •
transcription •
villous trophoblast •
differentiation
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