Abstract
Cystic fibrosis is the most common genetic disease among Caucasians and affects tissues including lung, pancreas and reproductive tracts. It has been shown that Endoplasmic Reticulum (ER) stress and heat shock response are two major deregulated functional modules related to CFTR dysfunction. To identify the impact of CFTR deletion during spermatogenesis, we examined the expression of spermiogenesis-related genes in the testis of CFTR mutant mice (CF mice). We confirmed expression changes of MSY2, a germ cell specific RNA binding protein, resulting from deletion of CFTR in testis. Furthermore, real time PCR and Western blot results showed that an inflammatory response was activated in CF mice testis, as reflected by the altered expression of cytokines. We demonstrate for the first time that expression of MSY2 is decreased in CF mice. Our results suggest that CFTR deletion in testis influences inflammatory responses and these features are likely to be due to the unique environment of the seminiferous tubule during the spermatogenesis process. The current study also suggests avenues to understand the pathophysiology of CFTR during spermatogenesis and provides targets for the possible treatment of CFTR-related infertility.
Highlights
Cystic fibrosis is a genetic disease caused by the mutation of Cystic fibrosis transmembrane conductance regulator (CFTR)
A CFTR defect in the testis affects MSY2 expression. It affects GRP78 as well as VDAC1 expression in testis and germ cells. This CFTR defect may be related to the overproduction of adenosine 50triphosphate (ATP) and ROS production, leading to altered expression of cytokines
Our results show that CFTR is a central regulator of spermatogenesis both in germ and Sertoli cells and CFTR defects will affect multiple aspects of spermatogenesis [3, 24]
Summary
Cystic fibrosis is a genetic disease caused by the mutation of Cystic fibrosis transmembrane conductance regulator (CFTR). European studies have shown that azoospermia patients have significantly higher 5T mutations compared with oligospermia patients, suggesting CFTR mutations could be related to defective spermatogenesis in humans [6, 7]. We have recently shown that CFTR deletion in CF mice causes spermatogenesis defects with compromised CREB activation in Sertoli cells. These constitute major CFTR-related pathways contributing to the phenotype of the pathophysiology [16, 17], among which GRP78 has emerged as a major heat shock protein involved in CFTR transport [18] These studies have provided insights into cystic fibrosis pathology from high-throughput approaches, it should be noted that the testis, which produces sperm, has a unique environment for CFTR function. Whether CFTR deletion in testis could lead to increased oxidative stress levels, leading to altered expression of cytokines were examined in CF mice model
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