The dual-specificity protein phosphatase DUSP9/MKP-4 is essential for placental function but is not required for normal embryonic development
The dual-specificity protein phosphatase DUSP9/MKP-4 is essential for placental function but is not required for normal embryonic development
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DOI：
10.1128/mcb.25.18.8323-8333.2005
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发表时间：
2005-09-01
影响因子：
5.3
通讯作者：
Keyse, SM
中科院分区：
文献类型：
--
作者：
Christie, GR;Williams, DJ;Keyse, SM
为了阐明DUSP 9（双特异性磷酸酶9），也称为MKP-4（丝裂原活化蛋白激酶[MAPK]磷酸酶4）的生理作用，在小鼠中删除了该基因。将雄性嵌合体与野生型雌性杂交产生杂合（DUSP 9（+/-））雌性。然而，当这些动物与野生型（DUSP 9（+/y））雄性杂交时，没有后代携带靶向DUSP 9等位基因，表明雌性杂合和雄性无效（DUSP 9（-/y））动物都在子宫内死亡。DUSP 9基因位于X染色体上，这种胚胎致死模式与小鼠胚胎外组织中父方X染色体的选择性失活一致，表明DUSP 9/MKP 4在胎盘发育过程中发挥重要作用。对妊娠后8至10.5天的胚胎进行的检查证实，致死性是由于迷路发育失败，这与滋养层巨细胞和胎盘迷路中DUSP 9/MKP-4的正常表达模式完全相关。最后，当胎盘缺陷被挽救时，雄性空（DUSP 9（-/y））胚胎发育到足月，表现正常，并且是可育的。我们的研究结果表明，DUSP 9/MKP-4是必不可少的胎盘器官发生，但在哺乳动物胚胎发育，并强调了双重特异性MAPK磷酸酶在调节脊椎动物的发育结果的关键作用。
To elucidate the physiological role(s) of DUSP9 (dual-specificity phosphatase 9), also known as MKP-4 (mitogen-activated protein kinase [MAPK] phosphatase 4), the gene was deleted in mice. Crossing male chimeras with wild-type females resulted in heterozygous (DUSP9(+/-)) females. However, when these animals were crossed with wild-type (DUSP9(+/y)) males none of the progeny carried the targeted DUSP9 allele, indicating that both female heterozygous and male null (DUSP9(-/y)) animals die in utero. The DUSP9 gene is on the X chromosome, and this pattern of embryonic lethality is consistent with the selective inactivation of the paternal X chromosome in the extraembryonic tissues of the mouse, suggesting that DUSP9/MKP4 performs an essential function during placental development. Examination of embryos between 8 and 10.5 days postcoitum confirmed that lethality was due to a failure of labyrinth development, and this correlates exactly with the normal expression pattern of DUSP9/MKP-4 in the trophoblast giant cells and labyrinth of the placenta. Finally, when the placental defect was rescued, male null (DUSP9(-/y)) embryos developed to term, appeared normal, and were fertile. Our results indicate that DUSP9/MKP-4 is essential for placental organogenesis but is otherwise dispensable for mammalian embryonic development and highlights the critical role of dual specificity MAPK phosphatases in the regulation of developmental outcomes in vertebrates.