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Basic helix-loop-helix transcription factor TCF21 is a downstream target of the male sex determining gene SRY.

Bhandari RK, Sadler-Riggleman I, Clement TM, Skinner MK - PLoS ONE (2011)

Bottom Line: SRY was found to directly associate with the Tcf21 promoter SRY/SOX9 response elements in vivo during fetal rat testis development.TCF21 was found to promote an in vitro sex reversal of embryonic ovarian cells to induce precursor Sertoli cell differentiation.TCF21 and SRY had similar effects on the in vitro sex reversal gonadal cell transcriptomes.

View Article: PubMed Central - PubMed

Affiliation: Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America.

ABSTRACT
The cascade of molecular events involved in mammalian sex determination has been shown to involve the SRY gene, but specific downstream events have eluded researchers for decades. The current study identifies one of the first direct downstream targets of the male sex determining factor SRY as the basic-helix-loop-helix (bHLH) transcription factor TCF21. SRY was found to bind to the Tcf21 promoter and activate gene expression. Mutagenesis of SRY/SOX9 response elements in the Tcf21 promoter eliminated the actions of SRY. SRY was found to directly associate with the Tcf21 promoter SRY/SOX9 response elements in vivo during fetal rat testis development. TCF21 was found to promote an in vitro sex reversal of embryonic ovarian cells to induce precursor Sertoli cell differentiation. TCF21 and SRY had similar effects on the in vitro sex reversal gonadal cell transcriptomes. Therefore, SRY acts directly on the Tcf21 promoter to in part initiate a cascade of events associated with Sertoli cell differentiation and embryonic testis development.

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Transcriptome analysis of SRY and TCF21 actions.Venn diagram (A) with overlap of total gene sets (p<0.05) altered inresponse to various expression constraints (Sry,Tcf21, Tcf21 plusTcf12, Tcf12). Total genes in thegene sets and overlap numbers are presented. These gene sets arestatistically significant increase genes, but with no further cut-offparameters. (B) Restricted gene sets overlapped in female E13 culturesinvolving gene sets with altered expression with >1.2 fold change,p<0.05, and mean difference >10.
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pone-0019935-g005: Transcriptome analysis of SRY and TCF21 actions.Venn diagram (A) with overlap of total gene sets (p<0.05) altered inresponse to various expression constraints (Sry,Tcf21, Tcf21 plusTcf12, Tcf12). Total genes in thegene sets and overlap numbers are presented. These gene sets arestatistically significant increase genes, but with no further cut-offparameters. (B) Restricted gene sets overlapped in female E13 culturesinvolving gene sets with altered expression with >1.2 fold change,p<0.05, and mean difference >10.

Mentions: The cell culture transcriptomes were examined to assess the invitro sex reversal of the embryonic ovarian cell culture to atestis cell differentiated state on a genome wide level. Microarray analysis ofthe embryonic cell cultures were investigated in the absence or presence of SRY,TCF21 or TCF21 with its potential binding partner TCF12/REB-alpha. All bHLHtranscription factors dimerize and due to the high level ofTcf12 expression in the embryonic testis (Figure 1), the combinedactions of TCF21 and TCF12 were also assessed. TCF12 is also known as REB-alphawhich is somewhat ubiquitously expressed and a binding partner of numerous bHLHfactors [19]. Over-expression of SRY in the embryonic ovary cellculture promoted a transcriptome more similar to the testis with approximately800 significantly increased transcripts, Figure 5A. Interestingly, TCF21 also promoteda transcriptome with approximately 20% overlap with that induced by Sry,Figure 5A. The combinedactions of TCF21 and TCF12 induced a more dramatic increase in AMH expression,data not shown, and a transcriptome with overlap with TCF21 and SRY, Figure 5. Observations supporta potential role for TCF12 as a potential partner for TCF21. A list of the geneswith the most highly increased expression induced by SRY and TCF21 are presentedin TableS1. An extended list of the genes altered after TCF21, SRY or TCF21and TCF12 over-expression are presented in Table S2.Observations demonstrate TCF21 and TCF12 promote some similarities in thein vitro sex reversal transition in the transcriptome asSRY, supporting a role of TCF21 as a downstream target of Sry during malegonadal sex determination.


Basic helix-loop-helix transcription factor TCF21 is a downstream target of the male sex determining gene SRY.

Bhandari RK, Sadler-Riggleman I, Clement TM, Skinner MK - PLoS ONE (2011)

Transcriptome analysis of SRY and TCF21 actions.Venn diagram (A) with overlap of total gene sets (p<0.05) altered inresponse to various expression constraints (Sry,Tcf21, Tcf21 plusTcf12, Tcf12). Total genes in thegene sets and overlap numbers are presented. These gene sets arestatistically significant increase genes, but with no further cut-offparameters. (B) Restricted gene sets overlapped in female E13 culturesinvolving gene sets with altered expression with >1.2 fold change,p<0.05, and mean difference >10.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3101584&req=5

pone-0019935-g005: Transcriptome analysis of SRY and TCF21 actions.Venn diagram (A) with overlap of total gene sets (p<0.05) altered inresponse to various expression constraints (Sry,Tcf21, Tcf21 plusTcf12, Tcf12). Total genes in thegene sets and overlap numbers are presented. These gene sets arestatistically significant increase genes, but with no further cut-offparameters. (B) Restricted gene sets overlapped in female E13 culturesinvolving gene sets with altered expression with >1.2 fold change,p<0.05, and mean difference >10.
Mentions: The cell culture transcriptomes were examined to assess the invitro sex reversal of the embryonic ovarian cell culture to atestis cell differentiated state on a genome wide level. Microarray analysis ofthe embryonic cell cultures were investigated in the absence or presence of SRY,TCF21 or TCF21 with its potential binding partner TCF12/REB-alpha. All bHLHtranscription factors dimerize and due to the high level ofTcf12 expression in the embryonic testis (Figure 1), the combinedactions of TCF21 and TCF12 were also assessed. TCF12 is also known as REB-alphawhich is somewhat ubiquitously expressed and a binding partner of numerous bHLHfactors [19]. Over-expression of SRY in the embryonic ovary cellculture promoted a transcriptome more similar to the testis with approximately800 significantly increased transcripts, Figure 5A. Interestingly, TCF21 also promoteda transcriptome with approximately 20% overlap with that induced by Sry,Figure 5A. The combinedactions of TCF21 and TCF12 induced a more dramatic increase in AMH expression,data not shown, and a transcriptome with overlap with TCF21 and SRY, Figure 5. Observations supporta potential role for TCF12 as a potential partner for TCF21. A list of the geneswith the most highly increased expression induced by SRY and TCF21 are presentedin TableS1. An extended list of the genes altered after TCF21, SRY or TCF21and TCF12 over-expression are presented in Table S2.Observations demonstrate TCF21 and TCF12 promote some similarities in thein vitro sex reversal transition in the transcriptome asSRY, supporting a role of TCF21 as a downstream target of Sry during malegonadal sex determination.

Bottom Line: SRY was found to directly associate with the Tcf21 promoter SRY/SOX9 response elements in vivo during fetal rat testis development.TCF21 was found to promote an in vitro sex reversal of embryonic ovarian cells to induce precursor Sertoli cell differentiation.TCF21 and SRY had similar effects on the in vitro sex reversal gonadal cell transcriptomes.

View Article: PubMed Central - PubMed

Affiliation: Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America.

ABSTRACT
The cascade of molecular events involved in mammalian sex determination has been shown to involve the SRY gene, but specific downstream events have eluded researchers for decades. The current study identifies one of the first direct downstream targets of the male sex determining factor SRY as the basic-helix-loop-helix (bHLH) transcription factor TCF21. SRY was found to bind to the Tcf21 promoter and activate gene expression. Mutagenesis of SRY/SOX9 response elements in the Tcf21 promoter eliminated the actions of SRY. SRY was found to directly associate with the Tcf21 promoter SRY/SOX9 response elements in vivo during fetal rat testis development. TCF21 was found to promote an in vitro sex reversal of embryonic ovarian cells to induce precursor Sertoli cell differentiation. TCF21 and SRY had similar effects on the in vitro sex reversal gonadal cell transcriptomes. Therefore, SRY acts directly on the Tcf21 promoter to in part initiate a cascade of events associated with Sertoli cell differentiation and embryonic testis development.

Show MeSH
Related in: MedlinePlus