Defective CFTR-Dependent CREB Activation Results in Impaired Spermatogenesis and Azoospermia

Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China.
PLoS ONE (Impact Factor: 3.23). 05/2011; 6(5):e19120. DOI: 10.1371/journal.pone.0019120
Source: PubMed


Cystic fibrosis (CF) is the most common life-limiting recessive genetic disease among Caucasians caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) with over 95% male patients infertile. However, whether CFTR mutations could affect spermatogenesis and result in azoospermia remains an open question. Here we report compromised spermatogenesis, with significantly reduced testicular weight and sperm count, and decreased cAMP-responsive element binding protein (CREB) expression in the testes of CFTR knockout mice. The involvement of CFTR in HCO(3) (-) transport and the expression of the HCO(3) (-) sensor, soluble adenylyl cyclase (sAC), are demonstrated for the first time in the primary culture of rat Sertoli cells. Inhibition of CFTR or depletion of HCO(3) (-) could reduce FSH-stimulated, sAC-dependent cAMP production and phosphorylation of CREB, the key transcription factor in spermatogenesis. Decreased CFTR and CREB expression are also observed in human testes with azoospermia. The present study reveals a previously undefined role of CFTR and sAC in regulating the cAMP-CREB signaling pathway in Sertoli cells, defect of which may result in impaired spermatogenesis and azoospermia. Altered CFTR-sAC-cAMP-CREB functional loop may also underline the pathogenesis of various CF-related diseases.

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    • "Boockfort and collaborators [7] have previously reported the CFTR presence in cultured SCs from Sprague–Dawley rats and it has been proposed that CFTR plays a crucial role in seminiferous fluid secretion and ionic composition [10] [24]. As could be expected, we were also able to detect the presence of the 156 bp product of CFTR mRNA in cultured rat SCs (Fig. 2, Panel A). "
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    ABSTRACT: Sertoli cells (SCs) form the blood-testis barrier (BTB) that controls the microenvironment where the germ cells develop. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role to male fertility and it was recently suggested that it may promote water transport. Interestingly, Aquaporin-4 (AQP4) is widely expressed in blood barriers, but was never identified in SCs. Herein we hypothesized that SCs express CFTR and AQP4 and that they can physically interact. Primary SCs cultures from 20-day-old rats were maintained and CFTR and AQP4 mRNA and protein expression was assessed by RT-PCR and western blot, respectively. The possible physical interaction between CFTR and AQP4 was studied by co-immunoprecipitation. We were able to confirm the presence of CFTR at mRNA and protein level in cultured rat SCs. AQP4 mRNA analysis showed that cultured rat SCs express the transcript variant c of AQP4, which was followed by immunodetection of the correspondent protein. The co-immunoprecipitation experiments showed a direct interaction between AQP4 and CFTR in cultured rat SCs. Our results suggest that CFTR physically interacts with AQP4 in rat SCs evidencing a possible mechanism by which CFTR can control water transport through BTB. The full enlightenment of this particular relation between CFTR and AQP4 may point towards possible therapeutic targets to counteract male subfertility/infertility in men with Cystic Fibrosis and mutations in CFTR gene, which are known to impair spermatogenesis due to defective water transport.
    Biochemical and Biophysical Research Communications 04/2014; 446(4). DOI:10.1016/j.bbrc.2014.03.046 · 2.30 Impact Factor
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    • "spermatogenesis (Trezise et al., 1993a; Trezise et al., 1993b; Xu et al., 2011b), sperm fertilizing capacity (Xu et al., 2007) and inflammatory response (Belcher & Vij, 2010; Buchanan et al., 2009; Campodonico et al., 2008; Mattoscio et al., 2010). The phenotypic severity of CF is essentially referable to CFTR residual function (Estivill, 1996; Zhang et al., 2009) that in turn depends on a combination of variables acting on the CFTR gene, transcript and/or protein, as well as to the action of variables external to CFTR. "

    Cystic Fibrosis - Renewed Hopes Through Research, 03/2012; , ISBN: 978-953-51-0287-8
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    ABSTRACT: PURPOSE: To evaluate five common cystic fibrosis trans-membrane conductance regulator (CFTR) mutations (ΔF508, G542X, R117H, W1282X and N1303K) in the Iranian infertile men with noncongenital absence of vas deferens (CAVD) obstructive azoospermia. METHODS: The common CFTR gene mutations were tested on blood samples from 53 infertile men with non-CAVD obstructive azoospermia and 50 normal men as control individuals. Genomic DNA is extracted from the whole blood and the common CFTR mutations have been detected by the amplification refractory mutation system (ARMS) techniques. RESULTS: The common CFTR mutations were found positive in 5/53)9.43%(for ΔF508 and 4/53)7.55%(for G542X mutation of all patients tested. Also, no CFTR mutations were detected in the normal men. CONCLUSION: The common CFTR mutations were detected in 9/53(17%) infertile men with non-CAVD obstructive azoospermia. Pre-treatment CFTR mutation analysis remains critical to distinguish cystic fibrosis (CF) genotypes for men with non CAVD obstructive azoospermia.
    Journal of Assisted Reproduction and Genetics 10/2011; 28(11). DOI:10.1007/s10815-011-9632-7 · 1.72 Impact Factor
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