Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect
Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect
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DOI：
10.1073/pnas.0400050101
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发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Gossen, JA
中科院分区：
文献类型：
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作者：
Esposito, G;Jaiswal, BS;Gossen, JA
为了获得受精的能力，精子经历了复杂的激活过程，但目前知之甚少。由碳酸氢盐依赖性可溶性腺苷酸环化酶（sAC）产生的细胞内cAMP升高被认为在启动精子成熟的级联事件中起核心作用。在这里，我们发现有针对性地破坏sAC基因不会影响精子发生，但会显著损害精子活力，导致男性不育。sAC突变精子的特点是完全丧失向前运动能力，不能在体外使卵母细胞受精。有趣的是，sAC突变精子的运动能力在cAMP负荷下可以恢复，这表明观察到的运动能力缺陷不是由结构缺陷引起的。因此，我们得出结论，sAC在控制运动的信号级联的激活中起着重要而非多余的作用，因此在生育中起作用。sAC在生育中的关键作用以及在sAC缺陷小鼠中没有任何其他明显的病理异常，可能为开发可作为人类男性避孕药的抑制剂提供了理论依据。
To acquire the ability to fertilize, spermatozoa undergo complex, but at present poorly understood, activation processes. The intracellular rise of cAMP produced by, the bicarbonate-dependent soluble adenylyl cyclase (sAC) has been suggested to play a central role in initiating the cascade of the events that culminates in spermatozoa maturation. Here, we show that targeted disruption of the sAC gene does not affect spermatogenesis but dramatically impairs sperm motility, leading to male sterility. sAC mutant spermatozoa are characterized by a total loss of forward motility and are unable to fertilize oocytes in vitro. Interestingly, motility in sAC mutant spermatozoa can be restored on cAMP loading, indicating that the motility defect observed is not caused by a structural defect. We, therefore, conclude that sAC plays an essential and nonredundant role in the activation of the signaling cascade controlling motility and, therefore, in fertility. The crucial role of sAC in fertility and the absence of any other obvious pathological abnormalities in sAC-deficient mice may provide a rationale for developing inhibitors that can be applied as a human male contraceptive.