14-3-3ε is important for neuronal migration by binding to NUDEL:: a molecular explanation for Miller-Dieker syndrome
14-3-3ε is important for neuronal migration by binding to NUDEL:: a molecular explanation for Miller-Dieker syndrome
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DOI：
10.1038/ng1169
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发表时间：
2003-07-01
期刊：
影响因子：
30.8
通讯作者：
Wynshaw-Boris, A
中科院分区：
文献类型：
--
作者：
Toyo-oka, K;Shionoya, A;Wynshaw-Boris, A
17p13.3杂合缺失导致人类神经元迁移障碍、孤立性无脑序列(ILS)和更严重的Miller-Dieker综合征(MDS)。PAFAH1B1(编码LIS1的基因)突变是导致ILS并导致MDS的原因，但更严重的MDS的遗传原因尚不清楚。在这里，我们发现编码14-3-3 epsilon(YWHAE)的基因在MDS患者中总是缺失的，YWHAE是一种普遍存在的磷酸丝氨酸/苏氨酸结合蛋白家族。YWhae基因缺陷的小鼠在大脑发育和神经元迁移方面存在缺陷，与Pafah1b1杂合子小鼠的缺陷相似。两个基因杂合子的小鼠比单一杂合子的小鼠有更严重的迁移缺陷。14-3-3epsilon与CDK5/p35磷酸化的Nudel结合，这种结合维持Nudel的磷酸化。与Lis1类似，14-3-3epsilon缺失导致Nudel和Lis1定位错误，与细胞质动力蛋白功能降低一致。这些结果证实了14-3-3 epsilon通过维持CDK5的磷酸化作用在神经元发育中的关键作用，并为17p13.3缺失的人类神经元迁移缺陷的严重程度的差异提供了分子解释。
Heterozygous deletions of 17p13.3 result in the human neuronal migration disorders isolated lissencephaly sequence (ILS) and the more severe Miller Dieker syndrome (MDS). Mutations in PAFAH1B1 (the gene encoding LIS1) are responsible for ILS and contribute to MDS, but the genetic causes of the greater severity of MDS are unknown. Here, we show that the gene encoding 14-3-3epsilon (YWHAE), one of a family of ubiquitous phosphoserine/threonine binding proteins, is always deleted in individuals with MDS. Mice deficient in Ywhae have defects in brain development and neuronal migration, similar to defects observed in mice heterozygous with respect to Pafah1b1. Mice heterozygous with respect to both genes have more severe migration defects than single heterozygotes. 14-3-3epsilon binds to CDK5/p35-phosphorylated NUDEL and this binding maintains NUDEL phosphorylation. Similar to LIS1, deficiency of 14-3-3epsilon results in mislocalization of NUDEL and LIS1, consistent with reduction of cytoplasmic dynein function. These results establish a crucial role for 14-3-3epsilon in neuronal development by sustaining the effects of CDK5 phosphorylation and provide a molecular explanation for the differences in severity of human neuronal migration defects with 17p13.3 deletions.