Nature Genetics
34, 274 - 285 (2003)
Published online: 8 June 2003; | doi:10.1038/ng1169
14-3-3 is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller−Dieker syndromeKazuhito Toyo-oka1, Aki Shionoya2, Michael J Gambello1, 5, Carlos Cardoso3, 5, Richard Leventer3, 5, Heather L Ward3, Ramses Ayala4, Li-Huei Tsai4, William Dobyns3, David Ledbetter3, Shinji Hirotsune2
& Anthony Wynshaw-Boris11
Departments of Pediatrics and Medicine, UCSD Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Drive, Mailstop 0627, La Jolla, California 92093-0627, USA. 2
Center for Genome Medical Science, Saitama Medical School PRESTO, Japan Science and Technology Corporation, Inariyama 1397-1, Yamane, Hidaka City, Saitama 350-1241, Japan. 3
Department of Human Genetics, The University of Chicago, 924 E. 57th St., Rm. R113, Chicago, Illinois 60637-1470, USA. 4
Department of Pathology, Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA. 5
Present addresses: Department of Pediatrics, Division of Medical Genetics, The University of Texas Health Science Center at Houston Medical School, Houston, Texas 77030, USA (M.J.G.); INSERM U491, Faculte de Medecine La Timone, 27 Bd. Jean Moulin, 13385 Marseille Cedex 05, France (C.C.); Department of Neurology & Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia (R.L.).
Correspondence should be addressed to Shinji Hirotsune shinjih@saitama-med.ac.jp or Anthony Wynshaw-Boris awynshawboris@ucsd.eduHeterozygous 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 14-3-3 (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. 14-3-3 binds to CDK5/p35-phosphorylated NUDEL and this binding maintains NUDEL phosphorylation. Similar to LIS1, deficiency of 14-3-3 results in mislocalization of NUDEL and LIS1, consistent with reduction of cytoplasmic dynein function. These results establish a crucial role for 14-3-3 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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