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J. Biol. Chem., Vol. 279, Issue 37, 38194-38200, September 10, 2004

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Male Mice That Do Not Express Group VIA Phospholipase A₂ Produce Spermatozoa with Impaired Motility and Have Greatly Reduced Fertility^*

Shunzhong Bao, David J. Miller¶, Zhongmin Ma||, Mary Wohltmann, Grace Eng**, Sasanka Ramanadham, Kelle Moley**, and John Turk

From the Mass Spectrometry Resource, Division of Endocrinology, Departments of Medicine and of ^**Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110, the ^¶Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801, and the ^||Division of Experimental Diabetes, Mount Sinai School of Medicine, New York, New York 10029

The Group VIA Phospholipase A₂ (iPLA₂) is the first recognized cytosolic Ca²⁺-independent PLA₂ and has been proposed to participate in arachidonic acid (20:4) incorporation into glycerophosphocholine lipids, cell proliferation, exocytosis, apoptosis, and other processes. To study iPLA₂ functions, we disrupted its gene by homologous recombination to generate mice that do not express iPLA₂. Heterozygous iPLA₂^+/– breeding pairs yield a Mendelian 1:2:1 ratio of iPLA₂^+/+, iPLA₂^+/–, and iPLA₂^–/– pups and a 1:1 male:female gender distribution of iPLA₂^–/– pups. Several tissues of wild-type mice express iPLA₂ mRNA, immunoreactive protein, and activity, and testes express the highest levels. Testes or other tissues of iPLA₂^–/– mice express no iPLA₂ mRNA or protein, but iPLA₂^–/– testes are not deficient in 20:4-containing glycerophosphocholine lipids, indicating that iPLA₂ does not play an obligatory role in formation of such lipids in that tissue. Spermatozoa from iPLA₂^–/– mice have reduced motility and impaired ability to fertilize mouse oocytes in vitro and in vivo, and inhibiting iPLA₂ with a bromoenol lactone suicide substrate reduces motility of wild-type spermatozoa in a time- and concentration-dependent manner. Mating iPLA₂^–/– male mice with iPLA₂^+/+, iPLA₂^+/–, or iPLA₂^–/– female mice yields only about 7% of the number of pups produced by mating pairs with an iPLA₂^+/+ or iPLA₂^+/– male, but iPLA₂^–/– female mice have nearly normal fertility. These findings indicate that iPLA₂ plays an important functional role in spermatozoa, suggest a target for developing male contraceptive drugs, and complement reports that disruption of the Group IVA PLA₂ (cPLA₂) gene impairs female reproductive ability.

Received for publication, June 10, 2004 , and in revised form, July 1, 2004.

^* This work was supported by National Institutes of Health Grants R37-DK34388, PO1-HL57278, P41-RR00954, P60-DK20579, and P30-DK56341 (to J. T.), Grant RO1-HD38311 (to D. J. M.), Grant R01-DK063076 (to Z. M.), and Grant HD40390 (to K. M.) and by an award from the American Diabetes Association (to S. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Box 8127, Washington University School of. Medicine, 660 S. Euclid, St. Louis, MO 63110. E-mail: jturk{at}wustl.edu.

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