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14-3-3ε is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller–Dieker syndrome

Abstract

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 14-3-3ε (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. 14-3-3ε binds to CDK5/p35-phosphorylated NUDEL and this binding maintains NUDEL phosphorylation. Similar to LIS1, deficiency of 14-3-3ε results in mislocalization of NUDEL and LIS1, consistent with reduction of cytoplasmic dynein function. These results establish a crucial role for 14-3-3ε 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.

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Figure 1: Extent of deletion and brain phenotype of individuals with ILS and MDS.
Figure 2: Production and phenotype of 14-3-3ε-mutant mice.
Figure 3: BrdU birthdating analysis identifies neuronal migration defects in 14-3-3ε-deficient mice.
Figure 4: Genetic link between Ywhae and Pafah1b1 during cortical and hippocampal migration.
Figure 5: Interaction of 14-3-3ε with NUDEL.
Figure 6: 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.
Figure 7: 14-3-3ε is important for normal localization of NUDEL, LIS1 and β-COP.

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Acknowledgements

We would like to thank P. LaPorte and J. Chung for technical support; J. Gleeson, M.G. Rosenfeld and M. Muramatsu for reagents and for providing valuable suggestions and discussion; and S. Hisanaga for providing baculoviruses of CDK5 and p35. A.W-B., D.H.L. and W.B.D. were supported by grants from the US National Institutes of Neurological Diseases and Stroke, an institutional grant from the Howard Hughes Medical Institute and University of California San Diego School of Medicine funds. S.H. was supported by PRESTO, Japan Science and Technology Corporation. M.J.G. was a physician research fellow of the Howard Hughes Medical Institute.

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Correspondence to Shinji Hirotsune or Anthony Wynshaw-Boris.

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Toyo-oka, K., Shionoya, A., Gambello, M. et al. 14-3-3ε is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller–Dieker syndrome. Nat Genet 34, 274–285 (2003). https://doi.org/10.1038/ng1169

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