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

Malki, Safia; Nef, Serge; Notarnicola, Cécile; Thevenet, Laurie; Gasca, Stéphan; Méjean, Catherine; Berta, Philippe; Poulat, Françis; Boizet-Bonhoure, Brigitte

doi:10.1038/sj.emboj.7600660

Cited by 197 publications

(200 citation statements)

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“…In mammals, the development of the male genital ridge is driven by pre-Sertoli cells which constitute the first cell line to commit to the male differentiation pathway and which are known to recruit other cell types to the male pathway through various signaling mechanisms (Martineau et al, 1997;Capel et al, 1999;Adams and McLaren, 2002;Malki et al, 2005). Characterization of the specific subset of genes differentially expressed in pre-Sertoli cells compared with the female genital ridge immediately after the moment of testicular sex determination should provide further understanding of the molecular mechanisms involved in these processes.…”

Section: Discussionmentioning

confidence: 99%

“…Within this cell population we identified genes known to be important for testes development or as preSertoli cell markers, including Sox9, Amh/Mis, Dhh, Sf1/Nr5a1, Gata4, Gata6, Dmrt1, Fgf9, and Ptgds (Ikeda et al, 1994;Bitgood et al, 1996;Kent et al, 1996;Morais da Silva et al, 1996;Ketola et al, 1999;Colvin et al, 2001;Adams and McLaren, 2002;Tevosian et al, 2002;Malki et al, 2005;Wilhelm et al, 2005). Notably, HybSRYp-RFP expressing cells did not express markers for germ cells, such as Oct4 and Ssea-1, or markers for endothelial cells, such as Ntrk3.…”

Section: Fluorescent Hybsryp-rfp Cells Express Presertoli Cells Markementioning

confidence: 99%

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Presumptive pre‐sertoli cells express genes involved in cell proliferation and cell signalling during a critical window in early testis differentiation

Cory

Boyer

Pilon

et al. 2007

Molecular Reproduction Devel

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In mammals, the pre-Sertoli cell of the male genital ridge is the first cell type to display sex specific differentiation and differential gene expression. The genetic cascade driving the differentiationof pre-Sertoli cells and ultimately testis formationis beginning to be unravelled, but many questions remain. A better understanding of the transcriptome of pre-Sertoli cells immediately after sex determination is essential in order to further understand this differentiationprocess. A mouse model expressing Red Fluorescent Protein (RFP) under the control of a hybrid mouse/pig SRY promoter (HybSRYp-RFP) was used to purify cells from embryonic day 12.0 (e12.0) male genital ridges. To compare the transcriptomes of HybSRYp-RFP cell populations versus age matched whole female genital ridges, RNA was extracted and used to generate molecular probes that were hybridized onto Affymetrix Mouse Genome 430 2.0 microarrays. The expression of genes considered markers for pre-Sertoli cells, including Sox9, Mis, Dhh and Fgf9 were identified within the HybSRYp-RFP expressing cell population, while markers for germ cells (Oct4, SSEA-1) and endothelial cells (Ntrk3) were not identified. In contrast, markers for ovarian somatic cell expression, including Fst and Bmp2, were identified as overexpressed within the ovarian cell population. In a general fashion, genes identified as 2.5-fold over expressed in HybSRYp-RFP expressing cells coded notably for cell signalling and extra cellular proteins. The expression of Sox10, Stc2, Fgf18, Fgf13 and Wnt6 were further characterized via whole mount in situ hybridization (WISH) on male and female genital ridges between e11.5 and e14.5. Sox10, Fgf18, Fgf13 and Stc2 gene expression was detected within the male genital ridges while Wnt6 was found diffusely within both the male and female genital ridges. These data represent the earliest comprehensive microarray expression analysis of purified presumptive pre-Sertoli cells available to date. Mol. Reprod. Dev. 74: 1491-1504, 2007

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Section: Discussionmentioning

confidence: 99%

Section: Fluorescent Hybsryp-rfp Cells Express Presertoli Cells Markementioning

confidence: 99%

Presumptive pre‐sertoli cells express genes involved in cell proliferation and cell signalling during a critical window in early testis differentiation

Cory

Boyer

Pilon

et al. 2007

Molecular Reproduction Devel

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“…(20,21) The functions of RUNX2 and SOX9 are controlled by transcriptional and posttranscriptional regulation, including ubiquitination, phosphorylation, and acetylation. (12,(22)(23)(24)(25)(26)(27)(28)(29)(30) The temporal and spatial overlap of RUNX2 and SOX9 expression during embryonic development indicates a close coordination between these two key transcription factors during bone formation. (1,10,31) Indeed, it has been found that SOX9 exerts a dominant function over RUNX2 in mesenchymal precursors.…”

Section: Introductionmentioning

confidence: 99%

SOX9 determines RUNX2 transactivity by directing intracellular degradation

Cheng

Genever

2010

Journal of Bone and Mineral Research

129

109

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Mesenchymal stem cell differentiation is controlled by the cooperative activity of a network of signaling mechanisms. Among these, RUNX2 and SOX9 are the major transcription factors for osteogenesis and chondrogenesis, respectively. Their expression is overlapped both temporally and spatially during embryogenesis. Here we have demonstrated that RUNX2 and SOX9 physically interact in intact cells and have confirmed that SOX9 can inhibit the transactivation of RUNX2. In addition, RUNX2 exerts reciprocal inhibition on SOX9 transactivity. In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dosedependent degradation of RUNX2. Although RUNX2 is normally degraded by the ubiquitin-proteasome pathway, we found that SOX9-mediated degradation was proteasome-independent but phosphorylation-dependent and required the presence of the RUNX2 Cterminal domain, which contains a nuclear matrix targeting sequence (NMTS). Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed b-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown. Consequently, the mechanisms by which SOX9 regulates RUNX2 function may underlie broader signaling pathways that can influence osteochondrogenesis and mesenchymal fate. ß

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“…La prostaglandine D2 est un facteur autocrine dans la formation de la gonade embryonnaire mâle Au cours du développement testiculaire, à 11,5 dpc (days post-coï-tum) chez la souris, la L-PGDS est spécifiquement exprimée dans les gonades mâles [31,32], dans les cellules germinales et les cellules de Sertoli [14,33,34], expression postérieure à celle de Sry et Sox9, les deux facteurs-clés de la détermination testiculaire [35,36]. Sur le plan moléculaire, avant le pic d'expression du gène Sry à 11,5 dpc, le transcrit Sox9 est très faiblement exprimé dans la gonade mâle ou femelle [37].…”

Section: Revuesunclassified

“…Lorsque le gène Sry atteint son pic d'expression à 11,5 dpc, le transcrit Sox9 augmente chez le mâle et de façon concomitante, la protéine Sox9 est transportée dans le noyau. Nous avons mis en évidence un rôle de la PGD2 dans l'induction de la translocation nucléaire de Sox9 dans les cellules de Sertoli [33] et dans l'activation de son expression (données non publiées et [31]). Par différentes études pharmacologiques, nous avons montré que l'accumulation nucléaire de Sox9 est médiée via le récepteur DP1 (Figure 2).…”

Section: Revuesunclassified