Deletion of ERK1 and ERK2 in the CNS Causes Cortical Abnormalities and Neonatal Lethality: Erk1 Deficiency Enhances the Impairment of Neurogenesis in Erk2-Deficient Mice
Deletion of ERK1 and ERK2 in the CNS Causes Cortical Abnormalities and Neonatal Lethality: Erk1 Deficiency Enhances the Impairment of Neurogenesis in Erk2-Deficient Mice
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DOI：
10.1523/jneurosci.2243-10.2011
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发表时间：
2011-01-19
影响因子：
5.3
通讯作者：
Kazama, Tomiei
中科院分区：
文献类型：
--
作者：
Satoh, Yasushi;Kobayashi, Yasushi;Kazama, Tomiei
通过细胞外信号调节激酶（ERK）的细胞内信号传导在调节包括CNS在内的多种组织中的细胞功能中是重要的。虽然ERK 1和ERK 2具有非常相似的底物谱和氨基酸序列，但Erk 1和Erk 2缺陷小鼠之间存在显著不同的表型。因此，这两种蛋白质是否是相互补偿的功能同源物，或者它们是否具有不同的功能。在这里，我们产生了双敲除小鼠缺乏Erk 2的中枢神经系统，与无处不在的纯合性缺失的Erk 1，并比较这些小鼠的表型与单基因Erk 2缺陷小鼠。虽然我们确实获得了双敲除的新生幼崽，但它们存活不超过1天。这些幼崽在分娩后表现正常。然而，它们在出生后6-7小时胃里就没有乳汁了。观察到不同部位和严重程度的脑内血肿。双基因敲除幼鼠的脑室区和胼胝体发育不充分。与对照组相比，双基因敲除小鼠某些脑区的神经元大小和核形态明显异常，而Erk 2缺陷仅引起轻度表型。这些结果表明，总ERK 1/2活性控制细胞行为，以确保适当的大脑发育。
Intracellular signaling through extracellular signal-regulated kinase (ERK) is important in regulating cellular functions in a variety of tissues including the CNS. Although ERK1 and ERK2 have a very similar substrate profile and amino acid sequences, there are strikingly different phenotypes between Erk1- and Erk2-deficient mice. Thus, the question arose as to whether these two proteins are functional homologs that compensate for each other, or whether they have distinct functions. Here, we generated double knock-out mice deficient for Erk2 in the CNS, with ubiquitous homozygous deletion of Erk1, and compared the phenotypes of these mice with those of monogenic Erk2-deficient mice. Although we did obtain double knock-out newborn pups, they survived for not >1 d. These pups appeared normal just after parturition. However, they had no milk in their stomachs even 6-7 h after birth. Intracerebral hemorrhages with varying location and severity were observed. The ventricular zones and corpus callosum of the double knock-out pups did not develop adequately. Neuronal size and nuclear morphology in some brain regions were markedly aberrant in the double knock-out pups compared with controls, while deficiency in Erk2 only caused a mild phenotype. These results suggest that total ERK1/2 activity governs cellular behaviors to ensure proper brain development.