Prostaglandin D₂ Regulates SOX9 Nuclear Translocation during Gonadal Sex Determination in Tammar Wallaby, <b><i>Macropus eugenii</i></b>

Abstract

Sex determination and sexual differentiation pathways are highly conserved between marsupials and eutherians. There are 2 different pathways of prostaglandin D₂ (PGD₂) synthesis: prostaglandin D synthase (PTGDS) and haematopoietic prostaglandin D synthase (HPGDS). PGD₂ regulates the subcellular localization of SOX9 during gonadal sexual differentiation. To investigate the function of PGD₂ in the tammar gonad, we cultured undifferentiated male gonads in the presence of the HPGDS inhibitor HQL-79 and female gonads with exogenous PGD₂ to mimic activation of the PTGDS-PGD₂ pathway. Tammar PTGDS and HPGDS have only 50% similarity with mouse and human orthologues, but functional domains are conserved. The expression of SOX9 was unchanged by the treatments in cultured gonads, but its subcellular localization was markedly affected. SOX9 remained cytoplasmic in the Sertoli cells of testes treated with HQL-79. Treated testes developed a thickened ovary-like surface epithelium. In contrast, SOX9 became nuclear in the granulosa cells of developing ovaries treated with PGD₂ and the surface epithelium was thin, as in testes. These results demonstrate that PGD₂ regulates the subcellular localization of SOX9 and subsequent gonadal development in the developing marsupial gonads, as it does in mice, and that it must have been an ancestral mechanism.

Cellular calcium and redox regulation: the mediator of vertebrate environmental sex determination?

“…For example, in mammals the testis‐inducing transcription factor (SOX9) must be translocated from the cytoplasm to the nucleus for normal testes development to occur. Otherwise, the developing gonads retain ovary‐like characteristics even when expression levels of SOX9 are maintained (Chen et al ., ). This process in mammals is regulated by the CaRe‐sensitive catabolite activator protein cyclic AMP (cAMP) and protein kinase A phosphorylation (Malki et al ., 2005 a , b ), and by Ca 2+ ‐calmodulin nuclear entry pathways (Hanover, Love & Prinz, ).…”

Gene expression of male pathway genes sox9 and amh during early sex differentiation in a reptile departs from the classical amniote model

“…A similar mechanism might prevent SOX9 in female P. vitticeps embryos from activating male pathway genes in the nucleus until after sox9 expression decreases later in female embryonic development. Next to estrogen, also the signalling molecule prostaglandin D2 was shown to induce nuclear import of SOX9 in mammals which induces male gonad development [ 91 – 93 ]. We cannot draw any conclusion for P. vitticeps , as the gene for the prostaglandin synthase (L-Pgds or H-Pgds) has not yet been annotated in its genome.…”