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Androgen-Induced Rhox Homeobox Genes Modulate the Expression of AR-Regulated Genes

ABSTRACT: Rhox5, the founding member of the reproductive homeobox on the X chromosome (Rhox) gene cluster, encodes a homeodomain-containing transcription factor that is selectively expressed in Sertoli cells, where it promotes the survival of male germ cells. To identify Rhox5-regulated genes, we generated 15P-1 Sertoli cell clones expressing physiological levels of Rhox5 from a stably transfected expression vector. Microarray analysis identified many genes altered in expression in response to Rhox5, including those encoding proteins controlling cell cycle regulation, apoptosis, metabolism, and cell-cell interactions. Fifteen of these Rhox5-regulated genes were chosen for further analysis. Analysis of Rhox5-null male mice indicated that at least 9 of these are Rhox5-regulated in the testes in vivo. Many of them have distinct postnatal expression patterns and are regulated by Rhox5 at different postnatal time points. Most of them are expressed in Sertoli cells, indicating that they are candidates to be directly regulated by Rhox5. Transfection analysis with expression vectors encoding different mouse and human Rhox family members revealed that the regulatory response of a subset of these Rhox5-regulated genes is both conserved and redundant. Given that Rhox5 depends on AR for expression in Sertoli cells, we examined whether some Rhox5-regulated genes are also regulated by androgen receptor (AR). We provide several lines of evidence that this is the case, leading us to propose that RHOX5 serves as a key intermediate transcription factor that directs some of the actions of AR in the testes.

ORGANISM(S): Mus musculus

PROVIDER: GSE18785 | GEO | 2009/10/29

SECONDARY ACCESSION(S): PRJNA121257

REPOSITORIES: GEO

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Project description:Spermatogenesis is dependent primarily on testosterone action on the Sertoli cells. Although the identification of testosterone-regulated target genes in Sertoli cells has been approached using microarray analysis to compare gene expression in mice with androgen receptor (AR) elimination in the Sertoli cells (SCARKO) and wild type mice, the analysis has been complicated by alteration of germ cell composition of the testis when pubertal or adult mice were used and differences in Sertoli-cell gene expression from those in adult when prepubertal mice were used. Since the testicular cell components of adult jsd (Utp14bjsd ,juvenile spermatogonial depletion) mice and SCARKO-jsd mice are essentially identical, consisting of only type A spermatogonia and somatic cells, comparisons of gene expression profiles between jsd and SCARKO-jsd testes would identify AR regulated genes in adult Sertoli cells, with minimum effects of cell number changes. Microarray analysis identified 161 genes as downregulated and 202 genes as upregulated in the SCARKO-jsd mice compared to jsd mice. Some of the genes identified in the previous studies, including Rhox5, Drd4, and Fhod3, were also AR-regulated in the jsd testes but others, such as proteases and components of junctional complexes, were not androgen regulated in our model. Surprisingly, a set of germ-cell-specific genes preferentially expressed in differentiated spermatogonia and meiotic cells, including Meig1, Sycp3, and Ddx4, were all upregulated about 2-fold in SCARKO-jsd testes, demonstrating that, although there was no significant differentiation to spermatocytes in SCARKO-jsd mice, AR-regulated genes in Sertoli cells are involved in the regulation of spermatogonial differentiation. Further gene ontogeny analysis revealed possible sets of genes whose expression changes may be involved in the disruption of Sertoli cell organization in SCARKO-jsd testes. Comparisons of gene expression profiles between the testis of jsd mice (n=3) and SCARKO-jsd mice (n=3).

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Androgen-Induced Rhox Homeobox Genes Modulate the Expression of AR-Regulated Genes

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