Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene
Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene
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DOI：
10.1128/mcb.20.24.9337-9345.2000
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发表时间：
2000-12-01
影响因子：
5.3
通讯作者：
Hassell, JA
中科院分区：
文献类型：
--
作者：
Laing, MA;Coonrod, S;Hassell, JA
PEA 3是转录调控蛋白Ets家族的一员，在小鼠胚胎发生过程中以独特的空间和时间模式表达;其过表达与人类和小鼠中HER 2介导的乳腺肿瘤发生呈正相关。为了确定PEA 3是否在发育和肿瘤发生中起作用，并揭示其正常的生理作用，我们通过在胚胎干细胞中的基因靶向产生缺乏功能性PEA 3的小鼠，PEA 3（-/-）小鼠由具有预期孟德尔频率的杂合杂交产生，揭示PEA 3对于胚胎发生是不稳定的。PEA 3突变小鼠没有表现出明显的表型，并且寿命正常。然而，PEA 3缺陷的雄性不能繁殖，PEA 3在几个雄性性器官中表达，但PEA 3-/-小鼠器官的大体和组织学分析显示无异常，PEA 3突变纯合子小鼠的精子发生和精子形成也正常，并且它们的精子能够在体外受精卵。PEA（-/-）雄性进行正常的交配行为，但它们没有设置交配栓，并且在与PEA 3（-/-）雄性交配的雌性的子宫中不能检测到精子。勃起可以诱发腹压在PEA 3缺陷的雄性小鼠，在体外实验的结果表明，阴茎海绵体PEA 3突变体男性分离放松响应乙酰胆碱。因此，PGA 3突变雄性的不育涉及海绵体平滑肌近端的机制或射精功能障碍。然而，PEA 3突变小鼠与具有这种缺陷的其他敲除小鼠在表型上是可区分的，从而为进一步研究雄性性功能障碍提供了独特的模型。
PEA3, a member of the Ets family of transcriptional regulatory proteins, is expressed in a unique spatial and temporal pattern during mouse embryogenesis; its overexpression is positively correlated with HER2-mediated breast tumorigenesis in both humans and mice. To determine whether PEA3 plays a part in development and oncogenesis and to uncover its normal physiological role, we generated mice lacking functional PEA3 by gene targeting in embryonic stem cells, PEA3(-/-) mice arose from heterozygous crosses with the expected Mendelian frequency, revealing that PEA3 is dispensable for embryogenesis. PEA3 mutant mice displayed no overt phenotype and lived a normal life span. However, PEA3-deficient males failed to reproduce, PEA3 is expressed in several male sexual organs, but gross and histological analyses of the organs from PEA3-/- mice revealed no abnormalities, Spermatogenesis and spermiogenesis also appeared normal in mice homozygous for the PEA3 mutation, and their sperm were capable of fertilizing eggs in vitro. PEA(-/-) males engaged in normal mating behavior, but they did not set copulatory plugs and sperm could not be detected in the uteri of females that had mated with PEA3(-/-) males. Erections could be evoked by abdominal pressure in PEA3-deficient male mice, and the results of in vitro experiments revealed that the corpus cavernosum isolated from PEA3 mutant males relaxed in response to acetylcholine. Therefore, the infertility of PGA3 mutant males involves either mechanisms proximal to the cavernosal smooth muscle or an ejaculatory dysfunction, However, PEA3 mutant mice are phenotypically distinguishable From other knockout mice with such deficits and thus provide a unique model for Further investigation of male sexual dysfunction.