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Cyclic nucleotide phosphodiesterase 3A–deficient mice as a model of female infertility
Silvia Masciarelli, … , Marco Conti, Vincent Manganiello
Silvia Masciarelli, … , Marco Conti, Vincent Manganiello
Published July 15, 2004
Citation Information: J Clin Invest. 2004;114(2):196-205. https://doi.org/10.1172/JCI21804.
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Article Reproductive biology

Cyclic nucleotide phosphodiesterase 3A–deficient mice as a model of female infertility

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Abstract

Since cAMP blocks meiotic maturation of mammalian and amphibian oocytes in vitro and cyclic nucleotide phosphodiesterase 3A (PDE3A) is primarily responsible for oocyte cAMP hydrolysis, we generated PDE3A-deficient mice by homologous recombination. The Pde3a–/– females were viable and ovulated a normal number of oocytes but were completely infertile, because ovulated oocytes were arrested at the germinal vesicle stage and, therefore, could not be fertilized. Pde3a–/– oocytes lacked cAMP-specific PDE activity, contained increased cAMP levels, and failed to undergo spontaneous maturation in vitro (up to 48 hours). Meiotic maturation in Pde3a–/– oocytes was restored by inhibiting protein kinase A (PKA) with adenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS) or by injection of protein kinase inhibitor peptide (PKI) or mRNA coding for phosphatase CDC25, which confirms that increased cAMP-PKA signaling is responsible for the meiotic blockade. Pde3a–/– oocytes that underwent germinal vesicle breakdown showed activation of MPF and MAPK, completed the first meiotic division extruding a polar body, and became competent for fertilization by spermatozoa. We believe that these findings provide the first genetic evidence indicating that resumption of meiosis in vivo and in vitro requires PDE3A activity. Pde3a–/– mice represent an in vivo model where meiotic maturation and ovulation are dissociated, which underscores inhibition of oocyte maturation as a potential strategy for contraception.

Authors

Silvia Masciarelli, Kathleen Horner, Chengyu Liu, Sun Hee Park, Mary Hinckley, Steven Hockman, Taku Nedachi, Catherine Jin, Marco Conti, Vincent Manganiello

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Role of PDE3A in oocyte maturation and female infertility. Pde3a–/– mice...
Role of PDE3A in oocyte maturation and female infertility. Pde3a–/– mice represent what we believe to be the first genetic model indicating that that PDE3A is necessary for meiotic resumption in mouse oocytes and that, in the absence of oocyte PDE3A, increased cAMP and the consequent disruption of cAMP-signaling can lead to female infertility, presumably via PKA-catalyzed phosphorylation of key regulatory effectors that result in inhibition of MPF/MAPK-induced oocyte maturation. Our results with PKA inhibitors, such as Rp-8-Br-cAMPS and PKI, are consistent with PKA playing a major role in maintaining meiotic arrest at prophase I and thereby preventing meiotic progression to metaphase II and consequent development of competency for fertilization. The apparently reversible nature of the meiotic arrest in Pde3a–/– oocytes clearly suggests, along with reported effects of PDE3 inhibitors, such as cilostamide, on oocyte maturation (22–27), that oocyte PDE3A could represent an excellent potential target for contraceptives.
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