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

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 upregulates 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.

Genomes of Ellobius species provide insight into the evolutionary dynamics of mammalian sex chromosomes

“…There may have been a genetic predisposition toward development of a new sex-determination system in the common ancestor (Bagheri-Fam et al 2012), explaining how such a rare event could occur twice in the same lineage. Sex determination can be viewed as a genetic battle between sexes.…”

“…Impaired SRY actions in the ancestor of both E. lutescens and E. talpinus, for example, due to mutations in the Sox9 promoter as has been suggested (Bagheri-Fam et al 2012), may have provided an opportunity for a new sex-determining system to evolve, going hand in hand with further deterioration of SRY functions. This paves the way for Y Chromosome loss.…”

Did sex chromosome turnover promote divergence of the major mammal groups?

“…The loss of the SRY sex determining mechanism seems to have been accompanied by changes in its target gene SOX9 that may have led to its upregulation in the absence of SRY 76.…”

Sex Reversal in Non-Human Placental Mammals

“…They found that all species of the genus display a 14-bp deletion that increases activity of TESCO in HEK293T cells (via generation of new transcription factor binding sites). They proposed a model whereby the deletion may have triggered upregulation of Sox9 in XX gonads leading to destabilization of the XX/XY sex determination system that has facilitated the evolution of Sry -independent sex determination mechanisms in some Ellobius species [Bagheri-Fam et al, 2012]. The novel TDF in Ellobius still remains to be identified.…”