DAX-1 and DAX-1A expression in human testicular tissues with primary spermatogenic failure.
ABSTRACT DAX-1 [dosage-sensitive sex reversal-adrenal hypoplasia congenital (AHC) critical region on the X chromosome gene 1; NR0B1] is an orphan nuclear receptor that acts as a transcriptional repressor in adrenal/gonadal development, steroidogenesis and probably spermatogenesis. An alternatively spliced form called DAX-1A (NR0B1A) has been described in several tissues including the testis, and in vitro studies have shown an inhibitory effect on DAX-1 transcriptional function. We aimed to study the mRNA and protein expression of DAX-1 in testicular tissues of 65 men with primary spermatogenic failure [complete Sertoli cell only syndrome (SCOS), focal SCOS, maturation arrest and mixed atrophy] compared with 33 controls with normal spermatogenesis. As a novel finding, we observed intense immunostaining, not only in the nucleus of Sertoli cells, but also in pachytene spermatocytes and round spermatids. The quantitative mRNA expression of DAX-1 and DAX-1A was similar between cases and controls and was not associated with the levels of gonadotrophins and steroids. Moreover, DAX-I transcript expression level was ∼750-fold higher than DAX-1A, and there was a strong positive correlation between them (r = 0.52; P< 0.001). We conclude that, in addition to Sertoli cells, DAX-1/DAX-1A is expressed in germ cells from spermatogonia to round spermatids. Besides, the similar mRNA expression of DAX-I and DAX-IA in testicular tissues from cases and controls does not support the involvement of DAX-1 in the etiology of primary spermatogenic failure. Finally, the low level of expression of the alternative transcriptional variant DAX-1A would not support its putative inhibitory function in vivo.
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ABSTRACT: AR3, a major one of androgen receptor (AR) splice variants, has been shown to play a pivotal role in concert with AR signalling in prostate cancer. The present study was undertaken to characterise the expression pattern of AR3 in normal and impaired spermatogenesis. Expression of AR3 mRNA showed significantly lower level in testicular tissues with impaired spermatogenesis when compared to normal tissues. This aberrant expression profile of AR3 in human pathological testes was further confirmed by immunoblotting analysis. Moreover, in situ hybridisation studies revealed that the transcripts of the gene were dominantly localised in the pachytene spermatocytes and round spermatids, suggesting a potential involvement of this transcriptional regulator in the auto-/paracrine regulation of meiotic and post-meiotic differentiation. This hypothesis was strengthened by the observation that AR3 mRNA expression was positively correlated to average seminiferous tubule score and was negatively correlated to serum FSH level. To the best of our knowledge, such a distinct expression profile of AR3 has not been reported previously in human testis. Overall, our data are suggestive of a novel site of action of AR3 during human spermatogenesis and should shed light on the complicated circuit composed of AR and its splice variants.Andrologia 10/2013; · 1.55 Impact Factor
- Journal of Assisted Reproduction and Genetics 05/2012; 29(8):811-6. · 1.82 Impact Factor
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ABSTRACT: 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 cell (SC). 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 metastatic-associated protein 2 (MTA2), a component of histone deacetylase (HDAC) and nucleosome-remodelling complexes, as a gene product induced directly by testosterone (T) or indirectly by FSH, is exclusively expressed in SC. Stimulation of SC with FSH is accompanied by up-regulation of MTA2 expression and enhancement of deacetylase activity. This effect requires the integrity of functional Ar. Furthermore, MTA2 is a potent corepressor of FSHR transcription, as it can recruit histone deacetylase-1 (HDAC1) onto 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 SC. From a clinical standpoint, deregualted expression of MTA2 in SC of human pathological testes negatively correlates to the deregulated level of serum FSH. Overall, our present results provide the first evidence that FSH/Ar/MTA2 cascade may serve as an indispensable negative feedback to modulate the transduction events of SC 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 SC.Journal of Biological Chemistry 10/2012; · 4.65 Impact Factor