Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model

Schauwaers, Kris; Gendt, Karel De; Saunders, Philippa T. K.; Atanassova, Nina; Haelens, Annemie; Callewaert, Leen; Moehren, Udo; Swinnen, Johannes V.; Verhoeven, Guido; Verrijdt, Guy; Claessens, Frank

doi:10.1073/pnas.0610814104

Cited by 105 publications

(86 citation statements)

References 55 publications

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“…A similar dissociation of AR downstream effects is observed in the recently described SPARKI (Specificity-affecting AR KnockIn) mouse model [128].…”

Section: Other Transgenic Models With Mutant Ar Alleles Affecting Sersupporting

confidence: 54%

“…4) The available list of putative target genes offers a basis to screen for genes that are also androgen regulated in other models and species and in this way to develop tools to study disturbed androgen action in experimental animals and in man. Androgen-regulated genes identified in the SCARKO model, for example, have proven useful to guide searches in the SPARKI model for genes that depend on selective or classical AREs [128].…”

Section: Main Conclusion From the Available Gene Profiling Studiesmentioning

confidence: 99%

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Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

Verhoeven¹,

Denolet²,

Swinnen³

et al. 2008

IEMAMC

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Androgens play a key role in the control of spermatogenesis and interference with their intratesticular secretion and action is a critical element in many contraceptive strategies. Nonetheless, the cellular and molecular mechanisms by which androgens control germ cell development remain poorly understood. Recent transgenic models in which the androgen receptor (AR) is selectively ablated in Sertoli cells show unambiguously that the Sertoli cell is the main target for androgen action in the control of spermatogenesis. A number of additional mouse models have been developed mimicking human diseases in which mutations of the AR cause disturbed fertility without affecting male development. Transcriptional profiling studies in mice with Sertoli cell-selective AR ablation and in some other experimental paradigms have tried to identify androgen-regulated genes relevant to the control of spermatogenesis. The overlap in genes identified in different studies is poor but this may be due mainly to dissimilarities in experimental setup. In all studies, relatively large numbers of genes rather than a few key genes seem to be affected by androgen action. Genes related to tubular restructuring, cell junction dynamics, cytoskeleton, solute transportation and vitamin A metabolism are prominently present. Although further work is obviously needed, it may be anticipated that these studies will result in the identification of subsets of genes that can be used as diagnostic tools as well as in the identification of targets for the development of novel contraceptives.

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“…A similar dissociation of AR downstream effects is observed in the recently described SPARKI (Specificity-affecting AR KnockIn) mouse model [128].…”

Section: Other Transgenic Models With Mutant Ar Alleles Affecting Sersupporting

confidence: 54%

Section: Main Conclusion From the Available Gene Profiling Studiesmentioning

confidence: 99%

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

Verhoeven¹,

Denolet²,

Swinnen³

et al. 2008

IEMAMC

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“…Furthermore, only Pak6 was strongly coexpressed with Gr in the dopaminergic regions (P < 0.01). Thus, AR and GR may share some, but not all, coregulators, much like the fact that AR binding sites may overlap, in part, with GR binding sites (27). These results indicate that we can use genome-wide spatial coexpression not only to analyze the relationship between the receptors and their targets but also to identify region-specific coregulators.…”

Section: Region-specificmentioning

confidence: 84%

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Mahfouz

Lelieveldt

Grefhorst

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Steroid receptors are pleiotropic transcription factors that coordinate adaptation to different physiological states. An important target organ is the brain, but even though their effects are well studied in specific regions, brain-wide steroid receptor targets and mediators remain largely unknown due to the complexity of the brain. Here, we tested the idea that novel aspects of steroid action can be identified through spatial correlation of steroid receptors with genome-wide mRNA expression across different regions in the mouse brain. First, we observed significant coexpression of six nuclear receptors (NRs) [androgen receptor (Ar), estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), glucocorticoid receptor (Gr), mineralocorticoid receptor (Mr), and progesterone receptor (Pgr)] with sets of steroid target genes that were identified in single brain regions. These coexpression relationships were also present in distinct other brain regions, suggestive of as yet unidentified coordinate regulation of brain regions by, for example, glucocorticoids and estrogens. Second, coexpression of a set of 62 known NR coregulators and the six steroid receptors in 12 nonoverlapping mouse brain regions revealed selective downstream pathways, such as Pak6 as a mediator for the effects of Ar and Gr on dopaminergic transmission. Third, Magel2 and Irs4 were identified and validated as strongly responsive targets to the estrogen diethylstilbestrol in the mouse hypothalamus. The brain-and genome-wide correlations of mRNA expression levels of six steroid receptors that we provide constitute a rich resource for further predictions and understanding of brain modulation by steroid hormones. neuroendocrinology | nuclear receptors | transcription regulation | estrogens | glucocorticoids S teroid receptors are part of the superfamily of nuclear receptors (NRs) that act as transcription factors regulating expression of numerous biologically important target genes (1). Their transcriptional activity is induced by steroid hormones, which respond to changed demands in terms of reproductive status, mineral balance, or stressful physical and psychological challenges. A crucial site of action is the brain, where these hormones have strong modulatory effects on physiological regulation, cognitive function, mood, and behavior. They do so by changing cellular responsiveness to a variety of neurotransmitters and peptides, and by inducing morphological changes (2, 3).Understanding the effects of steroid hormones on the brain faces the challenge to identify in as many as 900 different brain nuclei (4) both the highly cell-specific target genes that mediate the hormone effects (5, 6) and the signaling factors that mediate or influence steroid receptor signaling. The latter include proteins affecting prereceptor metabolism, interacting transcription factors (7), and downstream NR coregulator proteins (1). Even if the effects of steroid hormones are well-studied in specific regions (1, 8), overall, the brain steroid receptor targets and mediators ...

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“…Rhox5 is one of very few genes known to be directly regulated by AR in Sertoli cells and, to our knowledge, is the only known androgen-induced transcription factor gene expressed in Sertoli cells (41). Interestingly, its Pp harbors "selective" AREs that respond to AR and not other nuclear hormone receptors, based on studies in cell lines (3) and a knock-in mouse that expresses a form of AR only able to activate the transcription of promoters harboring "nonselective" AREs (56). Recently, we discovered that a subset of other Rhox genes is induced by androgen and AR in the MSC1 cell line (39); most of these genes also depend on AR in Sertoli cells for their expression in testes in vivo (our unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

GATA Factors and Androgen Receptor Collaborate To Transcriptionally Activate theRhox5Homeobox Gene in Sertoli Cells

Bhardwaj

Rao

Kaur

et al. 2008

Molecular and Cellular Biology

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How Sertoli-specific expression is initiated is poorly understood. Here, we address this issue using the proximal promoter (Pp) from the Rhox5 homeobox gene. Its Sertoli cell-specific expression is achieved, in part, through a negative regulatory element that inhibits Pp transcription in non-Sertoli cell lines. Complementing this negative regulation is positive regulation conferred by four androgen-response elements (AREs) that interact with the androgen receptor (AR), a nuclear hormone receptor expressed at high levels in Sertoli cells. A third control mechanism is provided by a consensus GATA-binding site that is crucial for Pp transcription both in vitro and in vivo. Several lines of evidence suggested that GATA factors and AR act cooperatively to activate Pp transcription: (i) the GATA-binding site crucial for Pp transcription is in close proximity to two of the AREs, (ii) GATA and AR form a complex with the Pp in vitro, (iii) overexpression of GATA factors rescued expression from mutant Pp constructs harboring defective AREs, and (iv) incubation of a Sertoli cell line with testosterone triggered corecruitment of AR and GATA4 to the Pp. Collectively, our results suggest that the Rhox5 gene achieves Sertoli cell-specific transcription using a combinatorial strategy involving negative and cooperative positive regulation.

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Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model

Cited by 105 publications

References 55 publications

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

GATA Factors and Androgen Receptor Collaborate To Transcriptionally Activate theRhox5Homeobox Gene in Sertoli Cells

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