Sertoli cell-specific expression of metastasis-associated protein 2 (MTA2) is required for transcriptional regulation of the follicle-stimulating hormone receptor (FSHR) gene during spermatogenesis
| Autor: | Yuan-Qiang Zhang, Xiaohong Wang, Jie Zhao, Teng Li, Wei Li, Jing Hu, Zhen Li, Jinshan Zhang, Chuchao Zhu, Shun Zhang |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Male medicine.medical_specialty endocrine system Biology Biochemistry Histone Deacetylases Rats Sprague-Dawley Follicle-stimulating hormone Mice Internal medicine medicine Animals Humans Receptor Spermatogenesis Molecular Biology Regulation of gene expression Sertoli Cells Gene Expression Regulation Developmental Cell Biology Middle Aged Sertoli cell Rats Androgen receptor Mice Inbred C57BL Repressor Proteins medicine.anatomical_structure Endocrinology Trans-Activators Receptors FSH Follicle Stimulating Hormone Follicle-stimulating hormone receptor Corepressor hormones hormone substitutes and hormone antagonists Deacetylase activity Developmental Biology |
| Zdroj: | The Journal of biological chemistry. 287(48) |
| ISSN: | 1083-351X |
| Popis: | Desensitization of FSH response by down-regulation of FSHR transcription is critical for FSH action.Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription.The FSH/Ar/MTA2 cascade may serve as an indispensable negative feedback mechanism to modulate FSH transduction events in Sertoli cells.Our findings provide new insights into mechanisms by which FSH is deregulated in male infertile patients. The effect of follicle-stimulating hormone (FSH) on spermatogenesis is modulated at a fundamental level by controlling the number of competent receptors present at the surface of Sertoli cells (SCs). One underlying mechanism is the down-regulation of the expression levels of the FSH receptor (FSHR) gene after exposure to FSH. Here we report that metastasis-associated protein 2 (MTA2), a component of histone deacetylase and nucleosome-remodeling complexes, as a gene product induced directly by testosterone or indirectly by FSH, is exclusively expressed in SCs. Stimulation of SCs with FSH is accompanied by up-regulation of MTA2 expression and enhancement of deacetylase activity. This effect requires the integrity of functional androgen receptor. Furthermore, MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. Abolishment of endogenous MTA2 by siRNA treatment disrupted the desensitization of the FSH response and thereafter impaired the FSH-dependent secretory function of SCs. From a clinical standpoint, deregulated expression of MTA2 in SCs of human pathological testes negatively correlates to the deregulated level of serum FSH. Overall, our present results provide the first evidence that the FSH/androgen receptor/MTA2 cascade may serve as an indispensable negative feedback mechanism to modulate the transduction events of SCs in response to FSH. These data also underscore an unexpected reproductive facet of MTA2, which may operate as a novel integrator linking synergistic actions of FSH and androgen signaling in SCs. |
| Databáze: | OpenAIRE |
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