Male mice that do not express group VIA phospholipase A2 produce spermatozoa with impaired motility and have greatly reduced fertility
Male mice that do not express group VIA phospholipase A2 produce spermatozoa with impaired motility and have greatly reduced fertility
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DOI：
10.1074/jbc.m406489200
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发表时间：
2004-09-10
影响因子：
4.8
通讯作者：
Turk, J
中科院分区：
文献类型：
--
作者：
Bao, SZ;Miller, DJ;Turk, J
VIA族磷脂酶A（2）（iPLA（2）β）是第一个被识别的胞质Ca 2+非依赖性PLA 2，并且已经被提出参与花生四烯酸（20：4）掺入甘油磷酸胆碱脂质、细胞增殖、胞吐、凋亡和其他过程。为了研究iPLA（2）β的功能，我们通过同源重组破坏其基因，以产生不表达iPLA（2）β的小鼠。杂合iPLA（2）beta（+/-）育种对产生孟德尔1：2：1比率的iPLA（2）beta（+/-）、iPLA（2）beta（+/-）和iPLA（2）beta（-/-）幼仔，以及1：1雄性：雌性性别分布的iPLA（2）beta（+/-）幼仔。野生型小鼠的几种组织表达iPLA（2）β mRNA、免疫反应蛋白和活性，睾丸表达水平最高。iPLA（2）beta（+/-）小鼠的睾丸或其他组织不表达iPLA（2）beta mRNA或蛋白质，但iPLA（2）beta（+/-）睾丸不缺乏含有20：4的甘油磷酸胆碱脂质，表明iPLA（2）beta在该组织中形成此类脂质中不起强制性作用。iPLA（2）beta（-/-）小鼠的精子在体外和体内的运动性降低，使小鼠卵母细胞受精的能力受损，用溴烯醇内酯自杀底物抑制iPLA（2）beta以时间和浓度依赖性方式降低野生型精子的运动性。iPLA（2）beta（-/-）雄性小鼠与iPLA（2）beta（+/-）、iPLA（2）beta（+/-）或iPLA（2）beta（-/-）雌性小鼠交配产生的幼崽数量仅为与iPLA（2）beta（+/-）或iPLA（2）beta（-/-）雄性小鼠交配产生的幼崽数量的约7%，但iPLA（2）beta（-/-）雌性小鼠具有几乎正常的生育能力。这些发现表明iPLA（2）β在精子中起着重要的功能作用，提示了开发男性避孕药物的靶点，并补充了IVA组PLA（2）（cPLA（2）α）基因的破坏会损害女性生殖能力的报道。
The Group VIA Phospholipase A(2) (iPLA(2)beta) 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 iPLA(2)beta functions, we disrupted its gene by homologous recombination to generate mice that do not express iPLA(2)beta. Heterozygous iPLA(2)beta(+/-) breeding pairs yield a Mendelian 1: 2: 1 ratio of iPLA(2)beta(+/-), iPLA(2)beta(+/-), and iPLA(2)beta(-/-) pups and a 1: 1 male: female gender distribution of iPLA(2)beta(+/-) pups. Several tissues of wild-type mice express iPLA(2)beta mRNA, immunoreactive protein, and activity, and testes express the highest levels. Testes or other tissues of iPLA(2)beta(+/-) mice express no iPLA(2)beta mRNA or protein, but iPLA(2)beta(+/-) testes are not deficient in 20: 4-containing glycerophosphocholine lipids, indicating that iPLA(2)beta does not play an obligatory role in formation of such lipids in that tissue. Spermatozoa from iPLA(2)beta(-/-) mice have reduced motility and impaired ability to fertilize mouse oocytes in vitro and in vivo, and inhibiting iPLA(2)beta with a bromoenol lactone suicide substrate reduces motility of wild-type spermatozoa in a time- and concentration-dependent manner. Mating iPLA(2)beta(-/-) male mice with iPLA(2)beta(+/-), iPLA(2)beta(+/-), or iPLA(2)beta(-/-) female mice yields only about 7% of the number of pups produced by mating pairs with an iPLA(2)beta(+/-) or iPLA(2)beta(-/-) male, but iPLA(2)beta(-/-) female mice have nearly normal fertility. These findings indicate that iPLA(2)beta plays an important functional role in spermatozoa, suggest a target for developing male contraceptive drugs, and complement reports that disruption of the Group IVA PLA(2) (cPLA(2)alpha) gene impairs female reproductive ability.