Homozygous Inactivation of Sox9 Causes Complete XY Sex Reversal in Mice1

Barrionuevo, Francisco; Bagheri‐Fam, Stefan; Klattig, Jürgen; Kist, Ralf; Taketo, Makoto Mark; Englert, Christoph; Scherer, Gerd

doi:10.1095/biolreprod.105.045930

Cited by 311 publications

(261 citation statements)

References 32 publications

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“…Many studies on testis-determining factors such as Dmrt1 and Sox9 have previously been conducted in mammals and birds (Barrionuevo et al, 2006;Smith et al, 2009). Dmrt1 445 appears to be involved in a certain type of XY sex reversal in humans (Bennett et al, 1993;Flejter et al, 1998;Raymond et al, 1999b;Veitia et al, 2001).…”

Section: Gsdf Induces Testis-differentiating In the Tilapiamentioning

confidence: 99%

Gonadal soma-derived factor (gsdf), a TGF-beta superfamily gene, induces testis differentiation in the teleost fish Oreochromis niloticus

Kaneko

Ijiri

Kobayashi

et al. 2015

Molecular and Cellular Endocrinology

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Highlights･ Gsdf is expressed predominantly in XY gonads in the Nile tilapia.･ Gsdf expression pattern shows sexual dimorphism before morphological differentiation.･ Gsdf expression is the earliest gene expression detected in testis differentiation.･ Overexpression of gsdf is sufficient to induce testis differentiation in XX tilapia.Abbreviations: transforming growth factor-beta (TGF-beta), gonadal soma-derived factor (gsdf), doublesex/mab-3-related transcription factor-1 (Dmrt1), days post-hatching (dph), quantitative one-step RT-PCR (qRT-PCR), in situ hybridization (ISH) 2 ABSTRACTThe Nile tilapia, Oreochromis niloticus, is a gonochoristic teleost fish with an XX/XY genetic system and is an excellent model for gonadal sex differentiation. In the present study, we screened novel genes that were expressed predominantly in either XY or XX undifferentiated gonads during the critical period for differentiation of gonads into ovaries or testes using 5 microarray screening. We focused on one of the isolated 12 candidate genes, #9475, which was an ortholog of gsdf (gonadal soma-derived factor), a member of the transforming growth factor-beta superfamily. #9475/gsdf showed sexual dimorphism in expression in XY gonads before any other testis differentiation-related genes identified in this species thus far. We also overexpressed the #9475/gsdf gene in XX tilapia, and XX tilapia bearing the #9475/gsdf gene 10 showed normal testis development, which suggests that #9475/gsdf plays an important role in male determination and/or differentiation in tilapia.

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Section: Gsdf Induces Testis-differentiating In the Tilapiamentioning

confidence: 99%

Gonadal soma-derived factor (gsdf), a TGF-beta superfamily gene, induces testis differentiation in the teleost fish Oreochromis niloticus

Kaneko

Ijiri

Kobayashi

et al. 2015

Molecular and Cellular Endocrinology

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“…SOX9 can antagonize β-catenin function in chondrocytes (Akiyama et al, 2004) and intestinal epithelium (Bastide et al, 2007), however its action on Wnt/β-catenin pathway in the developing gonad has not been thoroughly investigated so far. It is interesting to note that, in XY Sox9 -/-mice, in the presence of Sry, two ovarian genes, Wnt4 and Foxl2 are expressed (Barrionuevo et al, 2006), indicating that Sox9 alone maybe responsible for the downregulation of Wnt4 or Foxl2 in the XY gonad.…”

Section: Is Wnt/β-catenin the Proposed "Z" Factor?mentioning

confidence: 99%

Human SRY inhibits β-catenin-mediated transcription

Bernard

Sim

Knower

et al. 2008

The International Journal of Biochemistry & Cell Biology

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In most mammals, sex is determined by the presence or absence of the SRY gene. SRY encodes a DNA binding HMG-box transcription factor which, during embryogenesis, is the initial trigger of testis differentiation from the bipotential gonad, yet its precise mode of function remains unclear. In ovarian development, R-spondin1 and Wnt4 act through the Wnt/β-catenin signaling pathway to regulate TCF-dependent expression of unknown target genes and repress testis development. Conversely, SRY may be necessary to prevent the development of ovaries by inhibiting the action of ovarian-determining genes. We hypothesize that SRY prevents Wnt/β-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed β-catenin-mediated TCFdependent gene activation in the presence of a specific GSK3β inhibitor or an activated β-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of β-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit β-catenin; surprisingly four SRY sex reversed mutants with defective DNA binding activity showed near wild-type SRY inhibitory activity. Moreover the potent transactivator SRY-VP16 fusion protein also showed wild-type SRY inhibitory activity. Thus SRY inhibition of β-catenin involves neither DNA binding nor transactivation functions of SRY. β-catenin and SRY interact in-vitro and SRY expression triggered β-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits β-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.

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“…Indeed, studies have shown significant functional redundancy between these factors (Bylund et al, 2003;Cheung and Briscoe, 2003;Graham et al, 2003;Taylor and LaBonne, 2005;Kellerer et al, 2006). Within the male genital ridge, Sox8 and Sox9 gene expression are up-regulated as a consequence of Sry expression (Sekido et al, 2004) and influence male sex determination and pre-Sertoli cell differentiation (Sock et al, 2001;Takada and Koopman, 2003;Chaboisser et al, 2004;Barrionuevo et al, 2006). Several studies have shown that Sox8 and Molecular Reproduction and Development.…”

Section: Genital Ridge Expression Of Selectedmentioning

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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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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Homozygous Inactivation of Sox9 Causes Complete XY Sex Reversal in Mice1

Cited by 311 publications

References 32 publications

Gonadal soma-derived factor (gsdf), a TGF-beta superfamily gene, induces testis differentiation in the teleost fish Oreochromis niloticus

Gonadal soma-derived factor (gsdf), a TGF-beta superfamily gene, induces testis differentiation in the teleost fish Oreochromis niloticus

Human SRY inhibits β-catenin-mediated transcription

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

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