Defective CFTR-dependent CREB activation results in impaired spermatogenesis and azoospermia.
Defective CFTR-dependent CREB activation results in impaired spermatogenesis and azoospermia.
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DOI：
10.1371/journal.pone.0019120
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Chan HC
中科院分区：
文献类型：
--
作者：
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
囊性纤维化（CF）是白人中最常见的限制生命的隐性遗传病，由囊性纤维化跨膜传导调节因子（CFTR）突变引起，超过95%的男性患者不育。然而，CFTR突变是否会影响精子发生并导致无精子症仍然是一个悬而未决的问题。在这里，我们报告了CFTR基因敲除小鼠睾丸中精子发生受损，睾丸重量和精子数量显着减少，并且cAMP反应元件结合蛋白（CREB）表达减少。CFTR参与HCO 3 −转运和HCO 3 −传感器可溶性腺苷酸环化酶（sAC）的表达首次在大鼠支持细胞的原代培养中得到证实。抑制CFTR或消耗HCO 3 −可以减少FSH刺激的、sAC依赖的cAMP产生和CREB的磷酸化，CREB是精子发生中的关键转录因子。CFTR和CREB的表达在无精子症患者的睾丸中也有降低。本研究揭示了CFTR和sAC在支持细胞中调节cAMP-CREB信号通路的先前未定义的作用，其缺陷可能导致精子发生受损和无精子症。改变的CFTR-sAC-cAMP-CREB功能环也可能强调各种CF相关疾病的发病机制。
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 HCO3 − transport and the expression of the HCO3 − 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 HCO3 − 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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DOI：
10.1073/pnas.0400050101
发表时间：
2004-03-02
影响因子：
11.1
作者：
Esposito, G;Jaiswal, BS;Gossen, JA
通讯作者：
Gossen, JA
影响因子：
6.1
作者：
Mak, V;Zielenski, J;Jarvi, KA
通讯作者：
Jarvi, KA
影响因子：
5.4
作者：
De Cesare, D;Fimia, GM;Sassone-Corsi, P
通讯作者：
Sassone-Corsi, P
影响因子：
3.8
作者：
Ashby, J;Tinwell, H;Haseman, J
通讯作者：
Haseman, J
影响因子：
4
作者：
Hihnala, S;Kujala, M;Höglund, P
通讯作者：
Höglund, P