14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome.
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.
Toyo-oka
Kazuhito
K
Department of Pediatrics, UCSD Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Drive, Mailstop 0627, La Jolla, California 92093-0627, USA.
Shionoya
Aki
A
Gambello
Michael J
MJ
Cardoso
Carlos
C
Leventer
Richard
R
Ward
Heather L
HL
Ayala
Ramses
R
Tsai
Li-Huei
LH
Dobyns
William
W
Ledbetter
David
D
Hirotsune
Shinji
S
Wynshaw-Boris
Anthony
A
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D048948:14-3-3 Proteins; D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000002:abnormalities*; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D020756:Coatomer Protein / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D049452:Green Fluorescent Proteins; D006801:Humans; D007124:Immunoenzyme Techniques; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013577:Syndrome; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D020756:Coatomer Protein; D004791:Enzyme Inhibitors; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; C482983:YWHAE protein, human; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D051360:Cyclin-Dependent Kinase 5; D011493:Protein Kinase C; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C513190:Pafah1b1 protein, mouse; D010749:Phosphoprotein Phosphatases; D004398:Dyneins