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

Kazuhito Toyo-Oka, Aki Shionoya, Michael J. Gambello, Carlos Cardoso, Richard Leventer, Heather L. Ward, Ramses Ayala, Li Huei Tsai, William Dobyns, David Ledbetter, Shinji Hirotsune, Anthony Wynshaw-Boris

Research output: Contribution to journalArticlepeer-review

320 Scopus citations

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 NU DEL 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.

Original languageEnglish (US)
Pages (from-to)274-285
Number of pages12
JournalNature Genetics
Volume34
Issue number3
DOIs
StatePublished - Jul 1 2003
Externally publishedYes

Fingerprint Dive into the research topics of '14-3-3ε is important for neuronal migration by binding to NUDEL: A molecular explanation for Miller-Dieker syndrome'. Together they form a unique fingerprint.

Cite this