• PMID: 21625623
• Gene Name: CFTR
• Condition: Impaired spermatogenesis, Azoospermia
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Impaired spermatogenesis, Azoospermia

Defective CFTR-dependent CREB activation results in impaired spermatogenesis and azoospermia

Xu WM, Chen J, Chen H, Diao RY, Fok KL, Dong JD, Sun TT, Chen WY, Yu MK, Zhang XH, Tsang LL, Lau A, Shi QX, Shi QH, Huang PB, Chan HC.

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. FAU - Xu, Wen Ming AU - Xu WM AD - 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. FAU - Chen, Jing AU - Chen J FAU - Chen, Hui AU - Chen H FAU - Diao, Rui Ying AU - Diao RY FAU - Fok, Kin Lam AU - Fok KL FAU - Dong, Jian Da AU - Dong JD FAU - Sun, Ting Ting AU - Sun TT FAU - Chen, Wen Ying AU - Chen WY FAU - Yu, Mei Kuen AU - Yu MK FAU - Zhang, Xiao Hu AU - Zhang XH FAU - Tsang, Lai Ling AU - Tsang LL FAU - Lau, Ann AU - Lau A FAU - Shi, Qi Xian AU - Shi QX FAU - Shi, Qing Hua AU - Shi QH FAU - Huang, Ping Bo AU - Huang PB