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Regulation of male sex determination: genital ridge formation and Sry activation in mice.

Tanaka SS, Nishinakamura R - Cell. Mol. Life Sci. (2014)

Bottom Line: The somatic precursor of gonads, the genital ridge is formed at the mid-gestation stage and gives rise to one of two organs, a testis or an ovary.The fate of the genital ridge, which is governed by the differentiation of somatic cells into Sertoli cells in the testes or granulosa cells in the ovaries, further determines the sex of an individual and their germ cells.Here, we review the recent progress that has provided new insights into the mechanisms underlying genital ridge formation as well as the regulation of Sry expression and its functions in male sex determination of mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan, stanaka@kumamoto-u.ac.jp.

ABSTRACT
Sex determination is essential for the sexual reproduction to generate the next generation by the formation of functional male or female gametes. In mammals, primary sex determination is commenced by the presence or absence of the Y chromosome, which controls the fate of the gonadal primordium. The somatic precursor of gonads, the genital ridge is formed at the mid-gestation stage and gives rise to one of two organs, a testis or an ovary. The fate of the genital ridge, which is governed by the differentiation of somatic cells into Sertoli cells in the testes or granulosa cells in the ovaries, further determines the sex of an individual and their germ cells. Mutation studies in human patients with disorders of sex development and mouse models have revealed factors that are involved in mammalian sex determination. In most of mammals, a single genetic trigger, the Y-linked gene Sry (sex determination region on Y chromosome), regulates testicular differentiation. Despite identification of Sry in 1990, precise mechanisms underlying the sex determination of bipotential genital ridges are still largely unknown. Here, we review the recent progress that has provided new insights into the mechanisms underlying genital ridge formation as well as the regulation of Sry expression and its functions in male sex determination of mice.

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Related in: MedlinePlus

Model for Sry upregulation. Before the onset of Sry expression, a reduction in the H3K9me2 levels of the Sry locus is mediated by stage-specific upregulation of the H3K9 demethylase Jmjd1a, which may allow Sry upregulation by transcriptional factors. Interactions of Gata4 with its co-factor Fog2 are critical for Sry activation. Fog2 is upregulated in the coelomic epithelium by Six1 and Six4 before the onset of Sry expression. Gata4 is transiently activated by the Gadd45g-Map3k4-p38 MAPK pathway because of the stage-specific Gadd45g upregulation. Subsequently, the phosphorylated Gata4 and Fog2 protein complex may bind to the Sry promoter and activate Sry expression in a stage-specific manner. The Wt1+KTS isoform may contribute to the post-transcriptional regulation of Sry mRNA. The polycomb group gene Cbx2 is required for Sry upregulation, but the genetic interaction between Cbx2 and Sry is unclear. In addition, Cbx2 promotes Nr5a1 upregulation, and Nr5a1 is proposed to be one of the upstream regulators of Sry
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Fig3: Model for Sry upregulation. Before the onset of Sry expression, a reduction in the H3K9me2 levels of the Sry locus is mediated by stage-specific upregulation of the H3K9 demethylase Jmjd1a, which may allow Sry upregulation by transcriptional factors. Interactions of Gata4 with its co-factor Fog2 are critical for Sry activation. Fog2 is upregulated in the coelomic epithelium by Six1 and Six4 before the onset of Sry expression. Gata4 is transiently activated by the Gadd45g-Map3k4-p38 MAPK pathway because of the stage-specific Gadd45g upregulation. Subsequently, the phosphorylated Gata4 and Fog2 protein complex may bind to the Sry promoter and activate Sry expression in a stage-specific manner. The Wt1+KTS isoform may contribute to the post-transcriptional regulation of Sry mRNA. The polycomb group gene Cbx2 is required for Sry upregulation, but the genetic interaction between Cbx2 and Sry is unclear. In addition, Cbx2 promotes Nr5a1 upregulation, and Nr5a1 is proposed to be one of the upstream regulators of Sry

Mentions: Collectively, this recent progress has revealed the molecular network that governs Sry upregulation (Fig. 3). Before the onset of Sry expression, H3K9me2 levels are reduced in the Sry locus, which is mediated by stage-specific upregulation of Jmjd1a, allowing initiation of Sry expression by the transcriptional factors. Fog2 expression is also upregulated in the coelomic epithelium by Six1 and Six4 before the onset of Sry expression. Gata4 is transiently activated by the Gadd45g–Map3k4–p38 MAPK pathway. Subsequently, the phosphorylated Gata4 and Fog2 protein complex may bind to the Sry promoter and activate Sry expression in a stage-specific manner. In addition, the Wt1+KTS isoform may contribute to the post-transcriptional regulation of Sry mRNA (Fig. 3).Fig. 3


Regulation of male sex determination: genital ridge formation and Sry activation in mice.

Tanaka SS, Nishinakamura R - Cell. Mol. Life Sci. (2014)

Model for Sry upregulation. Before the onset of Sry expression, a reduction in the H3K9me2 levels of the Sry locus is mediated by stage-specific upregulation of the H3K9 demethylase Jmjd1a, which may allow Sry upregulation by transcriptional factors. Interactions of Gata4 with its co-factor Fog2 are critical for Sry activation. Fog2 is upregulated in the coelomic epithelium by Six1 and Six4 before the onset of Sry expression. Gata4 is transiently activated by the Gadd45g-Map3k4-p38 MAPK pathway because of the stage-specific Gadd45g upregulation. Subsequently, the phosphorylated Gata4 and Fog2 protein complex may bind to the Sry promoter and activate Sry expression in a stage-specific manner. The Wt1+KTS isoform may contribute to the post-transcriptional regulation of Sry mRNA. The polycomb group gene Cbx2 is required for Sry upregulation, but the genetic interaction between Cbx2 and Sry is unclear. In addition, Cbx2 promotes Nr5a1 upregulation, and Nr5a1 is proposed to be one of the upstream regulators of Sry
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4233110&req=5

Fig3: Model for Sry upregulation. Before the onset of Sry expression, a reduction in the H3K9me2 levels of the Sry locus is mediated by stage-specific upregulation of the H3K9 demethylase Jmjd1a, which may allow Sry upregulation by transcriptional factors. Interactions of Gata4 with its co-factor Fog2 are critical for Sry activation. Fog2 is upregulated in the coelomic epithelium by Six1 and Six4 before the onset of Sry expression. Gata4 is transiently activated by the Gadd45g-Map3k4-p38 MAPK pathway because of the stage-specific Gadd45g upregulation. Subsequently, the phosphorylated Gata4 and Fog2 protein complex may bind to the Sry promoter and activate Sry expression in a stage-specific manner. The Wt1+KTS isoform may contribute to the post-transcriptional regulation of Sry mRNA. The polycomb group gene Cbx2 is required for Sry upregulation, but the genetic interaction between Cbx2 and Sry is unclear. In addition, Cbx2 promotes Nr5a1 upregulation, and Nr5a1 is proposed to be one of the upstream regulators of Sry
Mentions: Collectively, this recent progress has revealed the molecular network that governs Sry upregulation (Fig. 3). Before the onset of Sry expression, H3K9me2 levels are reduced in the Sry locus, which is mediated by stage-specific upregulation of Jmjd1a, allowing initiation of Sry expression by the transcriptional factors. Fog2 expression is also upregulated in the coelomic epithelium by Six1 and Six4 before the onset of Sry expression. Gata4 is transiently activated by the Gadd45g–Map3k4–p38 MAPK pathway. Subsequently, the phosphorylated Gata4 and Fog2 protein complex may bind to the Sry promoter and activate Sry expression in a stage-specific manner. In addition, the Wt1+KTS isoform may contribute to the post-transcriptional regulation of Sry mRNA (Fig. 3).Fig. 3

Bottom Line: The somatic precursor of gonads, the genital ridge is formed at the mid-gestation stage and gives rise to one of two organs, a testis or an ovary.The fate of the genital ridge, which is governed by the differentiation of somatic cells into Sertoli cells in the testes or granulosa cells in the ovaries, further determines the sex of an individual and their germ cells.Here, we review the recent progress that has provided new insights into the mechanisms underlying genital ridge formation as well as the regulation of Sry expression and its functions in male sex determination of mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan, stanaka@kumamoto-u.ac.jp.

ABSTRACT
Sex determination is essential for the sexual reproduction to generate the next generation by the formation of functional male or female gametes. In mammals, primary sex determination is commenced by the presence or absence of the Y chromosome, which controls the fate of the gonadal primordium. The somatic precursor of gonads, the genital ridge is formed at the mid-gestation stage and gives rise to one of two organs, a testis or an ovary. The fate of the genital ridge, which is governed by the differentiation of somatic cells into Sertoli cells in the testes or granulosa cells in the ovaries, further determines the sex of an individual and their germ cells. Mutation studies in human patients with disorders of sex development and mouse models have revealed factors that are involved in mammalian sex determination. In most of mammals, a single genetic trigger, the Y-linked gene Sry (sex determination region on Y chromosome), regulates testicular differentiation. Despite identification of Sry in 1990, precise mechanisms underlying the sex determination of bipotential genital ridges are still largely unknown. Here, we review the recent progress that has provided new insights into the mechanisms underlying genital ridge formation as well as the regulation of Sry expression and its functions in male sex determination of mice.

Show MeSH
Related in: MedlinePlus