title: Defective CFTR-dependent CREB activation results in impaired spermatogenesis and azoospermia.
abstract: 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.
authors.affiliation: 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.
authors.forename: Wen Ming
authors.initials: WM
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Rui Ying
authors.initials: RY
authors.lastname: Diao
authors.forename: Kin Lam
authors.initials: KL
authors.lastname: Fok
authors.forename: Jian Da
authors.initials: JD
authors.lastname: Dong
authors.forename: Ting Ting
authors.initials: TT
authors.lastname: Sun
authors.forename: Wen Ying
authors.initials: WY
authors.lastname: Chen
authors.forename: Mei Kuen
authors.initials: MK
authors.lastname: Yu
authors.forename: Xiao Hu
authors.initials: XH
authors.lastname: Zhang
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.forename: Ann
authors.initials: A
authors.lastname: Lau
authors.forename: Qi Xian
authors.initials: QX
authors.lastname: Shi
authors.forename: Qing Hua
authors.initials: QH
authors.lastname: Shi
authors.forename: Ping Bo
authors.initials: PB
authors.lastname: Huang
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000328:Adult; D000818:Animals; D053713:Azoospermia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001639:Bicarbonates / Q000378:metabolism; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012708:Sertoli Cells / Q000378:metabolism / Q000473:pathology; D013091:Spermatogenesis / Q000502:physiology*; D055815:Young Adult
chemical_list: D001639:Bicarbonates; D017362:Cyclic AMP Response Element-Binding Protein; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D000262:Adenylyl Cyclases