Abstract
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.
Highlights
Desensitization of follicle-stimulating hormone (FSH) response by down-regulation of FSH receptor (FSHR) transcription is critical for FSH action
In another experimental setting, immunoblotting analysis demonstrated a single band of the target protein in the whole blot, and negative controls consisting of incubating samples with the preabsorbed primary antibody or omitting the primary antibody demonstrated an abolished expression of testicular metastasis-associated protein 2 (MTA2), suggesting that the commercial antibody employed in the present study did not cross-react with other proteins (Fig. 1B)
To determine whether the observed repression of FSHR transcription by MTA2 was associated with recruitment of histone deacetylase (HDAC) complexes in vivo, we examined the association between endogenous MTA2 and the components of HDAC by co-immunoprecipitation and Western blotting
Summary
Desensitization of FSH response by down-regulation of FSHR transcription is critical for FSH action. 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 underscore an unexpected reproductive facet of MTA2, which may operate as a novel integrator linking synergistic actions of FSH and androgen signaling in SCs. Since the first description of the Sertoli cell (SC)[4] in 1865, this cell has drawn much attention of researchers because it is the only somatic type possessing a close structural relationship with germ cells inside seminiferous tubules (1). The proposed analysis would pave the way for a better understanding of the potential role of this important chromatin modifier in testicular physiology
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