Mice Deficient for Soluble Adenylyl Cyclase Are Infertile because of a Severe Sperm-Motility Defect

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 eve...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-03, Vol.101 (9), p.2993-2998
Main Authors: Esposito, Gloria, Jaiswal, Byjay S., Xie, Fang, Magda A. M. Krajnc-Franken, Tamara J. A. A. Robben, Strik, Ankie M., Kuil, Cor, Ria L. A. Philipsen, van Duin, Marcel, Conti, Marco, Gossen, Jan A., Beavo, Joseph A.
Format: Article
Language:English
Subjects:
Adenylyl Cyclases - deficiency
Adenylyl Cyclases - genetics
Alleles
Animals
beta-Galactosidase - genetics
Biological Sciences
Cyclic AMP - metabolism
DNA Primers
Enzymes
Female
Female animals
Fertility
Fertilization - genetics
Fertilization in Vitro
Genes, Reporter
Genetics
Infertility
Infertility, Male - genetics
Male
Male animals
Mating behavior
Mice
Mice, Knockout
Mice, Transgenic
Oocytes
Oocytes - physiology
Polymerase Chain Reaction
Rodents
Sperm motility
Sperm Motility - genetics
Spermatids
Spermatozoa
Spermatozoa - enzymology
Testes
Testis - enzymology
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0400050101