SOX9 Regulates Expression of the Male Fertility Gene Ets Variant Factor 5 (ETV5) during Mammalian Sex Development

Dimuthu Alankarage, Rowena Lavery, Terje Svingen, Sabine Kelly, Louisa Ludbrook, Stefan Bagheri-Fam, Peter Koopman, Vincent Harley

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

In humans, dysregulation of the sex determining gene SRY-box 9 (SOX9) leads to disorders of sex devel-opment (DSD). In mice, knock-out of Sox9 prior to sex determination leads to XY sex reversal, while Sox9inactivation after sex determination leads to spermatogenesis defects. SOX9 specifies the differentiationand function of Sertoli cells from somatic cell precursors, which then orchestrate the development andmaintenance of other testicular cell types, largely through unknown mechanisms. Here, we describe anovel testicular target gene of SOX9, Ets variant factor 5 (ETV5), a transcription factor responsible formaintaining the spermatogonial stem cell niche. Etv5 was highly expressed in wild-type XY but not XXmouse fetal gonads, with ETV5 protein localized in the Sertoli cells, interstitial cells and germ cells of thetestis. In XY Sox9 knock-out gonads, Etv5 expression was strongly down-regulated. Similarly, knock-downof SOX9 in the human Sertoli-like cell line NT2/D1 caused a decrease in ETV5 gene expression. Transcrip-tomic analysis of NT2/D1 cells over-expressing SOX9 showed that ETV5 expression was increased inresponse to SOX9. Moreover, chromatin immunoprecipitation of these cells, as well as of embryonicmouse gonads, showed direct binding of SOX9 to ETV5 regulatory regions. We demonstrate that SOX9was able to activate ETV5 expression via a conserved SOX site in the 5´regulatory region, mutation ofwhich led to loss of activation. In conclusion, we present a novel target gene of SOX9 in the testis, andsuggest that SOX9 regulation of ETV5 contributes to the control of male fertility.
Original languageEnglish
JournalThe International Journal of Biochemistry & Cell Biology
Volume79
Pages (from-to)41-51
Number of pages11
ISSN1357-2725
DOIs
Publication statusPublished - 2016
Externally publishedYes

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