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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dobyns, W.B., Reiner, O., Carrozzo, R. & Ledbetter, D.H. Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. J. Am. Med. Assoc. 270, 2838–2842 (1993).
Dobyns, W.B., Curry, C.J., Hoyme, H.E., Turlington, L. & Ledbetter, D.H. Clinical and molecular diagnosis of Miller–Dieker syndrome. Am. J. Hum. Genet. 48, 584–594 (1991).
Dobyns, W.B., Elias, E.R., Newlin, A.C., Pagon, R.A. & Ledbetter, D.H. Causal heterogeneity in isolated lissencephaly. Neurology 42, 1375–1388 (1992).
Ledbetter, S.A., Kuwano, A., Dobyns, W.B. & Ledbetter, D.H. Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly. Am. J. Hum. Genet. 50, 182–189 (1992).
Chong, S.S. et al. A revision of the lissencephaly and Miller–Dieker syndrome critical regions in chromosome 17p13.3. Hum. Mol. Genet. 6, 147–155 (1997).
Reiner, O. et al. Isolation of a Miller–Dieker lissencephaly gene containing G protein β-subunit-like repeats. Nature 364, 717–721 (1993).
Lo Nigro, C. et al. Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller–Dieker syndrome. Hum. Mol. Genet. 6, 157–164 (1997).
Hirotsune, S. et al. Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nat. Genet. 19, 333–339 (1998).
Gambello, M.J. et al. Multiple dose dependent effects of Lis1 on cerebral cortical development. J. Neurosci. 23, 1719–1729 (2003).
Cahana, A. et al. Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization. Proc. Natl. Acad. Sci. USA 98, 6429–6434 (2001).
Wynshaw-Boris, A. & Gambello, M.J. LIS1 and dynein motor function in neuronal migration and development. Genes Dev. 15, 639–651 (2001).
Gupta, A., Tsai, L.-H. & Wynshaw-Boris, A. Life is a journey: a genetic look at neocortical development. Nat. Rev. Genet. 3, 342–355 (2002).
Morris, R.N. Nuclear migration: from fungi to the mammalian brain. J. Cell Biol. 148, 1097–1101 (2000).
Sasaki, S. et al. A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system. Neuron 28, 681–696 (2000).
Niethammer, M. et al. NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Neuron 28, 697–711 (2000).
Oshima, T. et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl. Acad. Sci. USA 93, 11173–11178 (1996).
Chae, T. et al. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18, 29–42 (1997).
Pilz, D.T. et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum. Mol. Genet. 7, 2029–2037 (1998).
Cardoso, C. et al. The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene. Hum. Mol. Genet. 9, 3019–3028 (2000).
Fu, H., Subramanian, R.R. & Masters, S.C. 14-3-3 proteins: structure, function, and regulation. Annu. Rev. Pharmacol. Toxicol. 40, 617–647 (2000).
Muslin, A.J. & Xing, H. 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell. Signal. 12, 703–709 (2000).
Tzivion, G. & Avruch, J. 14-3-3 proteins: active cofactors in cellular regulation by serine/threonine phosphorylation. J. Biol. Chem. 277, 3061–3064 (2002).
Muslin, A.J., Tanner, J.W., Allen, P.M. & Shaw, A.S. Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 84, 889–897 (1996).
Yaffe, M.B. et al. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91, 961–971 (1997).
Cardoso, C. et al. Refinement of a 400 kb critical region allows genotypic differentiation between isolated lissencephaly, Miller–Dieker syndrome and other phenotypes secondary to deletions of 17p13.3. Am. J. Hum. Genet. 72, 918–930 (2003).
Bermingham, J. et al. Tst-1/Oct-6/SCIP regulates a unique step in peripheral myelination and is required for normal respiration. Genes Dev. 10, 1751–1762 (1996).
Fleck, M.W. et al. Hippocampal abnormalities and enhanced excitability in a murine model of human lissencephaly. J. Neurosci. 20, 2439–2450 (2000).
Huang, D., Patrick, G., Moffat, J., Tsai, L.H. & Andrews, B. Mammalian Cdk5 is a functional homologue of the budding yeast Pho85 cyclin-dependent protein kinase. Proc. Natl. Acad. Sci. USA 96, 14445–14450 (1999).
Floyd, S.R. et al. Amphiphysin 1 binds the cyclin-dependent kinase (cdk) regulatory subunit p35 and is phosphorylated by dck5 and cdk2. J. Biol. Chem. 276, 8104–8110 (2001).
Smith, D.S. et al. Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1. Nat. Cell Biol. 2, 767–775 (2000).
Yan, X. et al. Human Nudel and NudE as regulators of cytoplasmic dynein in poleward protein transport along the mitotic spindle. Mol. Cell Biol. 23, 1239–1250 (2003).
Vincenz, C. & Dixit, V.M. 14-3-3 proteins associate with A20 in an isoform-specific manner and function both as chaperone and adapter molecules. J. Biol. Chem. 271, 20029–20034 (1996).
Van Der Hoeven, P.C., Van Der Wal, J.C., Ruurs, P., Van Dijk, M.C. & Van Blitterswijk, J. 14-3-3 isotypes facilitate coupling of protein kinase C-zeta to Raf-1: negative regulation by 14-3-3 phosphorylation. Biochem. J. 345, 297–306 (2000).
Chang, H.C. & Rubin, G.M. 14-3-3 epsilon positively regulates Ras-mediated signaling in Drosophila. Genes Dev. 11, 1132–1139 (1997).
Broadie, K., Rushton, E., Skoulakis, E.M. & Davis, R.L. Leonardo, a Drosophila 14-3-3 protein involved in learning, regulates presynaptic function. Neuron 19, 391–402 (1997).
Skoulakis, E.M. & Davis, R.L. Olfactory learning deficits in mutants for leonardo, a Drosophila gene encoding a 14-3-3 protein. Neuron 17, 931–944 (1996).
Faulkner, N.E. et al. A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nat. Cell Biol. 2, 784–791 (2000).
Liu, Z., Steward, R. & Luo, L. Drosophila Lis1 is required for neuroblast proliferation, dendritic elaboration and axonal transport. Nat. Cell Biol. 2, 776–783 (2000).
Feng, Y. et al. Interactions between LIS1 and mNudE, a central component of the centrosome, are required for CNS lamination. Neuron 28, 665–679 (2000).
Veeranna et al. Neuronal cyclin-dependent kinase-5 phosphorylation sites in neurofilament protein (NF-H) are dephosphorylated by protein phosphatase 2A. J. Neurochem. 64, 2681–2690 (1995).
Sontag, E. et al. Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A. Neuron 17, 1201–1207 (1996).
Price, N.E., Wadzinski, B. & Mumby, M.C. An anchoring factor targets protein phosphatase 2A to brain microtubules. Brain Res. Mol. Brain Res. 73, 68–77 (1999).
Sontag, E. et al. Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. J. Biol. Chem. 274, 25490–25498 (1999).
Lin, F.C. & Arndt, K.T. The role of Saccharomyces cerevisiae type 2A phosphatase in the actin cytoskeleton and entry into mitosis. EMBO J. 14, 2745–2759 (1995).
Gotz, J., Probst, A., Ehler, E., Hemmings, B. & Kues, W. Delayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit Cα. Proc. Natl. Acad. Sci. USA 95, 12370–12375 (1998).
Feller, S. et al. Physiological signals and oncogenesis mediated through Crk family adapter proteins. J. Cell Physiol. 177, 535–552 (1998).
Tsuda, M., Tanaka, S., Sawa, H., Hanafusa, H. & Nagashima, K. Signaling adaptor protein v-Crk activates rho and regulates cell motility in 3Y1 rat fibroblast cell line. Cell. Growth Differ. 13, 131–139 (2002).
Weinstein, D.E., Dobrenis, K. & Birge, R.B. Targeted expression of an oncogenic adaptor protein v-Crk potentiates axonal growth in dorsal root ganglia and motor neurons in vivo. Brain Res. Dev. Brain Res. 116, 29–39 (1999).
Hirotsune, S. et al. Genomic organization of the murine Miller–Dieker/lissencephaly region: conservation of linkage with the human region. Genome Res. 7, 625–634 (1997).
Sontag, E. Protein phosphatase 2A: the Trojan Horse of cellular signaling. Cell. Signal. 13, 7–16 (2001).
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng1169
This article is cited by
-
14–3-3ε: a protein with complex physiology function but promising therapeutic potential in cancer
Cell Communication and Signaling (2024)
-
Transcriptome analysis of the cerebral cortex of acrylamide-exposed wild-type and IL-1β-knockout mice
Archives of Toxicology (2024)
-
14–3-3 protein regulation of excitation–contraction coupling
Pflügers Archiv - European Journal of Physiology (2022)
-
Dysregulation of peripheral expression of the YWHA genes during conversion to psychosis
Scientific Reports (2020)
-
Tead transcription factors differentially regulate cortical development
Scientific Reports (2020)