View the Current Issue

Article

  • The EMBO Journal (2005) 24, 1798 - 1809
  • doi:10.1038/sj.emboj.7600660

Published online: 5 May 2005

Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation

Safia Malki1, Serge Nef2, Cécile Notarnicola1, Laurie Thevenet1, Stéphan Gasca1, Catherine Méjean1, Philippe Berta1, Francis Poulat1 and Brigitte Boizet-Bonhoure1

  1. Institut de Génétique Humaine, CNRS UPR1142, rue de la Cardonille, Montpellier Cedex, France
  2. Department of Genetic Medicine and Development, University of Geneva Medical School, rue Michel-Servet, Geneva, Switzerland

Correspondence to:

Brigitte Boizet-Bonhoure, Institut de Génétique Humaine, CNRS UPR1142, 141, rue de la Cardonille, Montpellier Cedex 5, 34396, France. Tel.: +33 4 99 61 99 40; Fax: +33 4 99 61 99 42; E-mail: boizet@igh.cnrs.fr

Received 12 October 2004; Accepted 5 April 2005

During mammalian gonadal development, nuclear import/export of the transcription factor SOX9 is a critical step of the Sry-initiated testis-determining cascade. In this study, we identify a molecular mechanism contributing to the SOX9 nuclear translocation in NT2/D1 cells, which is mediated by the prostaglandin D2 (PGD2) signalling pathway via stimulation of its adenylcyclase-coupled DP1 receptor. We find that activation of cAMP-dependent protein kinase A (PKA) induces phosphorylation of SOX9 on its two S64 and S181 PKA sites, and its nuclear localization by enhancing SOX9 binding to the nucleocytoplasmic transport protein importin beta. Moreover, in embryonic gonads, we detect a male-specific prostaglandin D synthase expression and an active PGD2 signal at the time and place of SOX9 expression. We thus propose a new step in the sex-determining cascade where PGD2 acts as an autocrine factor inducing SOX9 nuclear translocation and subsequent Sertoli cell differentiation.

  • Keywords:

    • cAMP signalling,
    • nuclear import,
    • prostaglandin D2,
    • Sertoli cells,
    • SOX9