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.

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

“…The complete abolishment of MTA2 immunoreactivity in the SCs of SCOS tubules is in good agreement with the previous report that in spermatogenesis impairment where spermatocytes were absent, the nuclei of all or most SCs showed an intense acetylation of histone H4, regardless of the origin of the pathology (39). In addition, an abnormally high level of serum FSH has been frequently reported in male infertile patients (40). Given that the concentration of FSH in the serum of non-seasonal breeding males is relatively constant, the regulation of the number of FSH receptors and their competency to bind FSH and transduce signal may be an important level of control of the action of FSH in males.…”

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

“…Cryptorchidism has been described in several patients with DAX1/NR0B1 mutations (84,(89)(90)(91), but it may be less frequent than in men born with CHH linked to KAL1/ANOS1 mutations (2,73,74,92). The severity of CHH in men with DAX1/NR0B1 mutations can differ within the same family (79,80,82 88,93).…”

The DAX1 mutation in a patient with hypogonadotropic hypogonadism and adrenal hypoplasia congenita causes functional disruption of induction of spermatogenesis

“…Recent data showed expression of DAX1 in germ cells [15]. Postmortem testicular examination performed at a 23 days-old newborn with AHC and transversion in exon 2 of DAX1 gene demonstrated a well-defined testis cord containing Sertoli cells, and germ cells surrounded by a interstitial region [4].…”

“…It encodes a 470-amino acid protein which belongs to the nuclear hormone receptor superfamily (called DAX1). DAX1 is expressed in the adrenal cortex, pituitary and hypothalamus, gonadal cells such as Leydig and Sertoli cells, theca and granulosa cells and in germ cells [15, 26]. …”