The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation.
Activation by the Y-encoded testis determining factor SRY and maintenance of expression of the Sox9 gene encoding the central transcription factor of Sertoli cell differentiation are key events in the mammalian sexual differentiation program. In the mouse XY gonad, SOX9 upregulates Fgf9, which initiates a Sox9/Fgf9 feedforward loop, and Sox9 expression is stimulated by the prostaglandin D2 (PGD2) producing lipocalin prostaglandin D synthase (L-PGDS, or PTDGS) enzyme, which accelerates commitment to the male pathway. In an attempt to decipher the genetic relationships between Sox9 and the L-Pgds/PGD2 pathway during mouse testicular organogenesis, we found that ablation of Sox9 at the onset or during the time window of expression in embryonic Sertoli cells abolished L-Pgds transcription. By contrast, L-Pgds(-/-) XY embryonic gonads displayed a reduced level of Sox9 transcript and aberrant SOX9 protein subcellular localization. In this study, we demonstrated genetically that the L-Pgds/PGD2 pathway acts as a second amplification loop of Sox9 expression. Moreover, examination of Fgf9(-/-) and L-Pgds(-/-) XY embryonic gonads demonstrated that the two Sox9 gene activity amplifying pathways work independently. These data suggest that, once activated and maintained by SOX9, production of testicular L-PGDS leads to the accumulation of PGD2, which in turn activates Sox9 transcription and nuclear translocation of SOX9. This mechanism participates together with FGF9 as an amplification system of Sox9 gene expression and activity during mammalian testicular organogenesis.
Department of Genetics and Development, Institut de Génétique Humaine CNRS UPR1142, Montpellier, France.
Brigitte
B
Moniot
Faustine
F
Declosmenil
Francisco
F
Barrionuevo
Gerd
G
Scherer
Kosuke
K
Aritake
Safia
S
Malki
Laetitia
L
Marzi
Anne
A
Cohen-Solal
Ina
I
Georg
Jürgen
J
Klattig
Christoph
C
Englert
Yuna
Y
Kim
Blanche
B
Capel
Naomi
N
Eguchi
Yoshihiro
Y
Urade
Brigitte
B
Boizet-Bonhoure
Francis
F
Poulat
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D054834:Lipocalins / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D015230:Prostaglandin D2 / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012708:Sertoli Cells / Q000166:cytology / Q000502:physiology*; D012733:Sex Differentiation / Q000502:physiology*; D051876:Sex-Determining Region Y Protein / Q000378:metabolism; D013737:Testis / Q000166:cytology / Q000196:embryology* / Q000254:growth & development
D051525:Fibroblast Growth Factor 9; D054834:Lipocalins; D055758:SOX9 Transcription Factor; D051876:Sex-Determining Region Y Protein; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2