TY - JOUR
T1 - 14-3-3ε is important for neuronal migration by binding to NUDEL
T2 - A molecular explanation for Miller-Dieker syndrome
AU - Toyo-Oka, Kazuhito
AU - Shionoya, Aki
AU - Gambello, Michael J.
AU - Cardoso, Carlos
AU - Leventer, Richard
AU - Ward, Heather L.
AU - Ayala, Ramses
AU - Tsai, Li Huei
AU - Dobyns, William
AU - Ledbetter, David
AU - Hirotsune, Shinji
AU - Wynshaw-Boris, Anthony
PY - 2003/7/1
Y1 - 2003/7/1
N2 - 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.
AB - 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.
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U2 - 10.1038/ng1169
DO - 10.1038/ng1169
M3 - Article
C2 - 12796778
AN - SCOPUS:0038757833
SN - 1061-4036
VL - 34
SP - 274
EP - 285
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -