Establishment of testis-specific SOX9 activation requires high-glucose metabolism in mouse sex differentiation

Matoba, Shogo; Hiramatsu, Ryuji; Kanai‐Azuma, Masami; Tsunekawa, Naoki; Harikae, Kyoko; Kawakami, Hayato; Kurohmaru, Masamichi; Kanai, Yoshikatsu

doi:10.1016/j.ydbio.2008.09.004

Cited by 43 publications

(38 citation statements)

References 48 publications

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“…These regulatory loops induce the activation of other downstream male pathway events, such as Amh expression, cell proliferation in the coelomic epithelium (see Glossary, Box 1), cell migration from the mesonephros (see Glossary, Box 1) and testis-specific glycogenesis (Martineau et al, 1997;Capel et al, 1999;Schmahl et al, 2000;Schepers et al, 2003;Matoba et al, 2005;Matoba et al, 2008).…”

Section: Primermentioning

confidence: 99%

Sry: the master switch in mammalian sex determination

2010

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SummarySRY, the mammalian Y-chromosomal testis-determining gene, induces male sex determination. Recent studies in mice reveal that the major role of SRY is to achieve sufficient expression of the related gene Sox9, in order to induce Sertoli cell differentiation, which in turn drives testis formation. Here, we discuss the cascade of events triggered by SRY and the mechanisms that reinforce the differentiation of the testes in males while actively inhibiting ovarian development.

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Section: Primermentioning

confidence: 99%

Sry: the master switch in mammalian sex determination

2010

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“…Inc.; 7.5 mM) (Bowles et al, 2006). The segment culture assay using anterior, middle and posterior segments of the genital ridge (Hiramatsu et al, 2003) and the gonad culture without adjacent mesonephros Matoba et al, 2008) were also initiated from the XX Tg gonads at 14-15 ts. In addition, under the present culture conditions of XX and XY genital ridges initiated at 11.5 d.p.c., the gonadal explants at the 1st, 3rd and 5th day after culture roughly correspond to the testes/ovaries at 12.0-12.5, 13.5-14.5 and 15.5 d.p.c., respectively (Byskov, 1978;Taketo and Koide, 1981;Kanai et al, 1991;Mizukami et al, 2008;Hiramatsu et al, 2003;Hiramatsu et al, 2009;Hiramatsu et al, 2010;Wu et al, 2013).…”

Section: Organ Culturementioning

confidence: 99%

Heterogeneity in sexual bipotentiality and plasticity of granulosa cells in developing mouse ovaries

Harikae

Miura

Shinomura

et al. 2013

Journal of Cell Science

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SummaryIn mammalian sex determination, SRY directly upregulates the expression of SOX9, the master regulatory transcription factor in Sertoli cell differentiation, leading to testis formation. Without SRY action, the bipotential gonadal cells become pre-granulosa cells, which results in ovarian follicle development. When, where and how pre-granulosa cells are determined to differentiate into developing ovaries, however, remains unclear. By monitoring SRY-dependent SOX9 inducibility (SDSI) in an Sry-inducible mouse system, we were able to identify spatiotemporal changes in the sexual bipotentiality/plasticity of ovarian somatic cells throughout life. The early pre-granulosa cells maintain the SDSI until 11.5 d.p.c., after which most pre-granulosa cells rapidly lose this ability by 12.0 d.p.c. Unexpectedly, we found a subpopulation of the pre-granulosa cells near the mesonephric tissue that continuously retains SDSI throughout fetal and early postnatal stages. After birth, these SDSI-positive pre-granulosa cells contribute to the initial round of folliculogenesis by the secondary follicle stage. In experimental sex reversal of 13.5-d.p.c. ovaries grafted into adult male nude mice, the differentiated granulosa cells re-acquire the SDSI before other signs of masculinization. Our data provide direct evidence of an unexpectedly high sexual heterogeneity of granulosa cells in developing mouse ovaries in a stage-and region-specific manner. Discovery of such sexually bipotential granulosa cells provides a novel entry point to the understanding of masculinization in various cases of XX disorders of sexual development in mammalian ovaries.

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“…Besides this, feedforward pathways of Sox9 gene expression with the classic FGF9 signaling pathway (Kim et al, 2006) and, more recently, with a high-glucose metabolic state through an extracellular matrix (ECM) (Matoba et al, 2008), were shown to be necessary for the maintenance of Sox9 transcription and subsequently for Sertoli cell differentiation and testis cord formation. In this study, we have revealed that the PGD2 signaling pathway is likely to act independently of FGF9, thus implicating two independent feedforward loops between Sox9/Fgf9 (Kim et al, 2006) and Sox9/L-Pgds in the coordination of growth, cell differentiation and morphogenesis of the gonad.…”

Section: Research Articlementioning

confidence: 99%

The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation

et al. 2009

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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.

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Establishment of testis-specific SOX9 activation requires high-glucose metabolism in mouse sex differentiation

Cited by 43 publications

References 48 publications

Sry: the master switch in mammalian sex determination

Sry: the master switch in mammalian sex determination

Heterogeneity in sexual bipotentiality and plasticity of granulosa cells in developing mouse ovaries

The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation

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