Sox9 gene regulation and the loss of the XY/XX sex-determining mechanism in the mole vole Ellobius lutescens

Stefan Bagheri-Fam, Rajini Sreenivasan, Pascal Bernard, Kevin C Knower, Ryohei Sekido, Robin Lovell-Badge, Walter Just, Vincent R Harley

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

In most mammals, the Y chromosomal Sry gene initiates testis formation within the bipotential gonad, resulting in male development. SRY is a transcription factor and together with SF1 it directly up-regulates the expression of the pivotal sex-determining gene Sox9 via a 1.3-kb cis-regulatory element (TESCO) which contains an evolutionarily conserved region (ECR) of 180 bp. Remarkably, several rodent species appear to determine sex in the absence of Sry and a Y chromosome, including the mole voles Ellobius lutescens and Ellobius tancrei, whereas Ellobius fuscocapillus of the same genus retained Sry. The sex-determining mechanisms in the Sry-negative species remain elusive. We have cloned and sequenced 1.1 kb of E. lutescens TESCO which shares 75% sequence identity with mouse TESCO indicating that testicular Sox9 expression in E. lutescens might still be regulated via TESCO. We have also cloned and sequenced the ECRs of E. tancrei and E. fuscocapillus. While the three Ellobius ECRs are highly similar (94-97% sequence identity), they all display a 14-bp deletion (Δ14) removing a highly conserved SOX/TCF site. Introducing Δ14 into mouse TESCO increased both basal activity and SF1-mediated activation of TESCO in HEK293T cells. We propose a model whereby Δ14 may have triggered up-regulation of Sox9 in XX gonads leading to destabilization of the XY/XX sex-determining mechanism in Ellobius. E. lutescens/E. tancrei and E. fuscocapillus could have independently stabilized their sex determination mechanisms by Sry-independent and Sry-dependent approaches, respectively.

Original languageEnglish
Pages (from-to)191-199
Number of pages9
JournalChromosome Research
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 2012

Fingerprint

Arvicolinae
Genes
Gonads
Up-Regulation
sry Genes
Y Chromosome
Testis
Mammals
Rodentia
Transcription Factors

Keywords

  • animals
  • arvicolinae
  • base sequence
  • binding sites
  • cloning, molecular
  • conserved sequence
  • evolution, molecular
  • female
  • gene expression regulation
  • genetic variation
  • genetic vectors
  • HEK293 cells
  • humans
  • male
  • mice
  • models, genetic
  • molecular sequence data
  • mutagenesis, site-directed
  • SOX9 transcription factor
  • sequence alignment
  • sequence analysis, DNA
  • sequence deletion
  • sex determination processes
  • testis
  • Y chromosome

Cite this

Bagheri-Fam, S., Sreenivasan, R., Bernard, P., Knower, K. C., Sekido, R., Lovell-Badge, R., ... Harley, V. R. (2012). Sox9 gene regulation and the loss of the XY/XX sex-determining mechanism in the mole vole Ellobius lutescens. Chromosome Research, 20(1), 191-199. https://doi.org/10.1007/s10577-011-9269-5

Sox9 gene regulation and the loss of the XY/XX sex-determining mechanism in the mole vole Ellobius lutescens. / Bagheri-Fam, Stefan; Sreenivasan, Rajini; Bernard, Pascal; Knower, Kevin C; Sekido, Ryohei; Lovell-Badge, Robin; Just, Walter; Harley, Vincent R.

In: Chromosome Research, Vol. 20, No. 1, 01.2012, p. 191-199.

Research output: Contribution to journalArticle

Bagheri-Fam, S, Sreenivasan, R, Bernard, P, Knower, KC, Sekido, R, Lovell-Badge, R, Just, W & Harley, VR 2012, 'Sox9 gene regulation and the loss of the XY/XX sex-determining mechanism in the mole vole Ellobius lutescens', Chromosome Research, vol. 20, no. 1, pp. 191-199. https://doi.org/10.1007/s10577-011-9269-5
Bagheri-Fam, Stefan ; Sreenivasan, Rajini ; Bernard, Pascal ; Knower, Kevin C ; Sekido, Ryohei ; Lovell-Badge, Robin ; Just, Walter ; Harley, Vincent R. / Sox9 gene regulation and the loss of the XY/XX sex-determining mechanism in the mole vole Ellobius lutescens. In: Chromosome Research. 2012 ; Vol. 20, No. 1. pp. 191-199.
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AU - Sreenivasan, Rajini

AU - Bernard, Pascal

AU - Knower, Kevin C

AU - Sekido, Ryohei

AU - Lovell-Badge, Robin

AU - Just, Walter

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AB - In most mammals, the Y chromosomal Sry gene initiates testis formation within the bipotential gonad, resulting in male development. SRY is a transcription factor and together with SF1 it directly up-regulates the expression of the pivotal sex-determining gene Sox9 via a 1.3-kb cis-regulatory element (TESCO) which contains an evolutionarily conserved region (ECR) of 180 bp. Remarkably, several rodent species appear to determine sex in the absence of Sry and a Y chromosome, including the mole voles Ellobius lutescens and Ellobius tancrei, whereas Ellobius fuscocapillus of the same genus retained Sry. The sex-determining mechanisms in the Sry-negative species remain elusive. We have cloned and sequenced 1.1 kb of E. lutescens TESCO which shares 75% sequence identity with mouse TESCO indicating that testicular Sox9 expression in E. lutescens might still be regulated via TESCO. We have also cloned and sequenced the ECRs of E. tancrei and E. fuscocapillus. While the three Ellobius ECRs are highly similar (94-97% sequence identity), they all display a 14-bp deletion (Δ14) removing a highly conserved SOX/TCF site. Introducing Δ14 into mouse TESCO increased both basal activity and SF1-mediated activation of TESCO in HEK293T cells. We propose a model whereby Δ14 may have triggered up-regulation of Sox9 in XX gonads leading to destabilization of the XY/XX sex-determining mechanism in Ellobius. E. lutescens/E. tancrei and E. fuscocapillus could have independently stabilized their sex determination mechanisms by Sry-independent and Sry-dependent approaches, respectively.

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