Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation.
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.
Malki
Safia
S
Institut de Génétique Humaine, CNRS UPR1142, 141 rue de la Cardonille, Montpellier Cedex 5, France.
Nef
Serge
S
Notarnicola
Cécile
C
Thevenet
Laurie
L
Gasca
Stéphan
S
Méjean
Catherine
C
Berta
Philippe
P
Poulat
Francis
F
Boizet-Bonhoure
Brigitte
B
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D006609:High Mobility Group Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D009924:Organ Culture Techniques; D010053:Ovary / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D055758:SOX9 Transcription Factor; D013737:Testis / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D006609:High Mobility Group Proteins; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D014157:Transcription Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015230:Prostaglandin D2