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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development
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Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development

机译：丝裂原激活的蛋白激酶激酶激酶4（MEKK4）的丧失导致凋亡增加和神经管发育不良

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摘要

Neural tube defects (NTDs) are prevalent human birth defects. Mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK), are implicated in facilitating neural tube closure, yet upstream regulators remain to be identified. Here, we show that MAP kinase kinase kinase 4 (MEKK4) is strongly expressed in the developing neuroepithelium. Mice deficient in MEKK4 develop highly penetrant NTDs that cannot be rescued by supplementation with folic acid or inositol. Unlike most mouse models of NTDs, MEKK4 mutant embryos display genetically co-segregated exencephaly and spina bifida, recapitulating the phe-notypes observed in human patients. To identify downstream targets of MEKK4 during neural tube development, we examined the activity of MAP kinase kinase 4 (MKK4), a signaling intermediate between MAP kinase kinase kinase and JNK/p38. We found a significant reduction in MKK4 activity in MEKK4-deficient neuroepithelium at sites of neural tube closure. MAPK pathways are key regulators of cell apoptosis and proliferation. Analyses of the neuroepithelium in MEKK4-deficient embryos showed massively elevated apoptosis before and during neural tube closure, suggesting an antiapoptotic role for MEKK4 during development. In contrast, proliferation of MEKK4-deficient neuroepithelial cells appeared to be largely unaffected. MEKK4 therefore plays a critical role in regulating MKK4 activity and apoptotic cell death during neural tube development. Disruption of this signaling pathway may be clinically relevant to folate-resistant human NTDs.
机译：神经管缺陷（NTD）是普遍存在的人类出生缺陷。促分裂原活化蛋白激酶（MAPK），如c-Jun N端激酶（JNK），与促进神经管闭合有关，但上游调节子仍有待确定。在这里，我们显示MAP激酶激酶激酶4（MEKK4）在正在发育的神经上皮细胞中强烈表达。缺乏MEKK4的小鼠会形成高渗透性NTD，无法通过补充叶酸或肌醇来挽救。与大多数NTD小鼠模型不同，MEKK4突变体胚胎表现出遗传共分离的脑电图和脊柱裂，重现了在人类患者中观察到的phe型。为了确定神经管发育过程中MEKK4的下游目标，我们检查了MAP激酶激酶4（MKK4）的活性，MAP激酶激酶4是MAP激酶激酶激酶和JNK / p38之间的信号传导中间物。我们发现在神经管闭合部位，MEKK4缺陷型神经上皮细胞的MKK4活性显着降低。 MAPK途径是细胞凋亡和增殖的关键调节因子。对MEKK4缺陷型胚胎中神经上皮的分析显示，在神经管闭合之前和期间细胞凋亡大量升高，表明MEKK4在发育过程中具有抗凋亡作用。相反，MEKK4缺陷型神经上皮细胞的增殖似乎未受影响。因此，MEKK4在神经管发育过程中在调节MKK4活性和凋亡细胞死亡中起关键作用。该信号传导途径的破坏在临床上可能与抗叶酸的人NTD有关。

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