Profiling spermatogenic failure in adult testes bearing Sox9-deficient Sertoli cells identifies genes involved in feminization, inflammation and stress

Aurélie Lardenois,Philippe Demougin,Michael Primig,Frédéric Chalmel,Francisco Barrionuevo,Gerd Scherer

doi:10.1186/1477-7827-8-154

Abstract

BackgroundSox9 (Sry box containing gene 9) is a DNA-binding transcription factor involved in chondrocyte development and sex determination. The protein's absence in testicular Sertoli nurse cells has been shown to disrupt testicular function in adults but little is known at the genome-wide level about molecular events concomitant with testicular break-down.MethodsTo determine the genome-wide effect on mRNA concentrations triggered by the absence of Sox9 in Sertoli cells we analysed adult testicular tissue from wild-type versus mutant mice with high-density oligonucleotide microarrays and integrated the output of this experiment with regulatory motif predictions and protein-protein network data.ResultsWe report the genome-wide mRNA signature of adult testes lacking Sox9 in Sertoli cells before and after the onset of late spermatogenic failure as compared to fertile controls. The GeneChip data integrated with evolutionarily conserved Sox9 DNA binding motifs and regulatory network data identified genes involved in feminization, stress response and inflammation.ConclusionsOur results extend previous observations that genes required for female gonadogenesis are up-regulated in the absence of Sox9 in fetal Sertoli cells to the adult stage. Importantly, we identify gene networks involved in immunological processes and stress response which is reminiscent of a phenomenon occurring in a sub-group of infertile men. This suggests mice lacking Sox9 in their Sertoli cells to be a potentially useful model for adult human testicular failure.

Highlights

Sox9 (Sry box containing gene 9) is a DNA-binding transcription factor involved in chondrocyte development and sex determination
Samples from both backgrounds were first taken at 90 dpp prior to the onset of the phenotype where testes from Sox9flox/flox and AMH-Cre Sox9flox/flox mice are morphologically and histologically indistinguishable
We found that the promoters of these genes - for which we find strong signals in purified Sertoli cells, spermatogonia and ovary but not in testis - were statistically significantly enriched for conserved target sites of Sox9 (Figure 3A-C, Methods)

Summary

Introduction

Sox (Sry box containing gene 9) is a DNA-binding transcription factor involved in chondrocyte development and sex determination. Sex differentiation of mammalian males is controlled by the Y-chromosomal locus Sry (Sex-determining region of Y-chromosome) which, in cooperation with Steroidogenic factor 1 (Sf1), directly activates the expression of Sox9 [1]; for review, see [2] This protein is an important transcription factor involved in various developmental processes and pathologies [3]. Human SOX9 was found to be mutated in patients suffering from campomelic dysplasia, a condition linked with abnormal skeletal development and, critically, perturbed male gonadogenesis or complete sex reversal [13,14] This is in keeping with an important role for the rodent Sox protein in murine male gonad development initially suggested on the basis of its expression pattern [5,6]. Nothing is known about the global impact of Sox9’s absence in adult Sertoli cells at the molecular level [19]

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