Home LiteratureArticle Details
PMID: 20510931 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Two cyclin-dependent kinase pathways are essential for polarized trafficking of presynaptic components.

Cell ·Vol. 141 ·No. 5 ·2010-05-28 ·Pages 846-58

Ou CY, Poon VY, Maeder CI, Watanabe S, Lehrman EK, Fu AK, Park M, Fu WY, Jorgensen EM, Ip NY, Shen K

Abstract

Polarized trafficking of synaptic proteins to axons and dendrites is crucial to neuronal function. Through forward genetic analysis in C. elegans, we identified a cyclin (CYY-1) and a cyclin-dependent Pctaire kinase (PCT-1) necessary for targeting presynaptic components to the axon. Another cyclin-dependent kinase, CDK-5, and its activator p35, act in parallel to and partially redundantly with the CYY-1/PCT-1 pathway. Synaptic vesicles and active zone proteins mostly mislocalize to dendrites in animals defective for both PCT-1 and CDK-5 pathways. Unlike the kinesin-3 motor, unc-104/Kif1a mutant, cyy-1 cdk-5 double mutants have no reduction in anterogradely moving synaptic vesicle precursors (SVPs) as observed by dynamic imaging. Instead, the number of retrogradely moving SVPs is dramatically increased. Furthermore, this mislocalization defect is suppressed by disrupting the retrograde motor, the cytoplasmic dynein complex. Thus, PCT-1 and CDK-5 pathways direct polarized trafficking of presynaptic components by inhibiting dynein-mediated retrograde transport and setting the balance between anterograde and retrograde motors.

MeSH Terms
Animals Axons Caenorhabditis elegans Caenorhabditis elegans Proteins/metabolism Cyclin-Dependent Kinases/metabolism Cyclins/metabolism Kinesins/metabolism Neurons Signal Transduction Synapses/metabolism
Chemicals
Caenorhabditis elegans Proteins Cyclins Cyclin-Dependent Kinases Kinesins
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Ou Chan-Yen
Department of Biology, Howard Hughes Medical Institute, Stanford University, 385 Serra Mall, California 94305, USA.
Poon Vivian Y
Maeder Celine I
Watanabe Shigeki
Lehrman Emily K
Fu Amy K Y
Park Mikyoung
Fu Wing-Yu
Jorgensen Erik M
Ip Nancy Y
Shen Kang
References (54)
54 references, click to expand
  1. Mutations in Caenorhabditis elegans cytoplasmic dynein components reveal specificity of neuronal retrograde cargo.
    J Neurosci. 2004 Apr 21;24(16):3907-16 PMID: 15102906
  2. Regulation of the CDK-related protein kinase PCTAIRE-1 and its possible role in neurite outgrowth in Neuro-2A cells.
    J Cell Sci. 2002 Sep 1;115(Pt 17):3479-90 PMID: 12154078
  3. Cdk5 selectively affects the migration of different populations of neurons in the developing spinal cord.
    J Comp Neurol. 2007 Jul 10;503(2):297-307 PMID: 17492640
  4. Open syntaxin docks synaptic vesicles.
    PLoS Biol. 2007 Aug;5(8):e198 PMID: 17645391
  5. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5.
    Nature. 1994 Sep 29;371(6496):419-23 PMID: 8090221
  6. A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system.
    Neuron. 2000 Dec;28(3):681-96 PMID: 11163259
  7. Molecular motors and mechanisms of directional transport in neurons.
    Nat Rev Neurosci. 2005 Mar;6(3):201-14 PMID: 15711600
  8. The molecular motor toolbox for intracellular transport.
    Cell. 2003 Feb 21;112(4):467-80 PMID: 12600311
  9. Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex.
    J Neurosci. 1998 Aug 15;18(16):6370-7 PMID: 9698328
  10. Increased expression of cyclin D2 during multiple states of growth arrest in primary and established cells.
    Mol Cell Biol. 1998 Jun;18(6):3163-72 PMID: 9584157
  11. Cyclin-dependent kinase 5 permits efficient cytoskeletal remodeling--a hypothesis on neuronal migration.
    Cereb Cortex. 2006 Jul;16 Suppl 1:i64-8 PMID: 16766709
  12. Pctaire1 phosphorylates N-ethylmaleimide-sensitive fusion protein: implications in the regulation of its hexamerization and exocytosis.
    J Biol Chem. 2006 Apr 14;281(15):9852-8 PMID: 16461345
  13. Systematic analysis of genes required for synapse structure and function.
    Nature. 2005 Jul 28;436(7050):510-7 PMID: 16049479
  14. Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite.
    Proc Natl Acad Sci U S A. 1988 Nov;85(21):8335-9 PMID: 3054884
  15. Cyclin E is expressed in neurons and forms complexes with cdk5.
    Neuroreport. 1995 May 30;6(8):1130-2 PMID: 7662893
  16. Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK.
    Neuron. 2007 Dec 6;56(5):823-37 PMID: 18054859
  17. DNA transformation.
    Methods Cell Biol. 1995;48:451-82 PMID: 8531738
  18. The phosphorylation of kinesin regulates its binding to synaptic vesicles.
    J Biol Chem. 1992 Nov 25;267(33):23930-6 PMID: 1429730
  19. Cytoplasmic dynein-associated structures move bidirectionally in vivo.
    J Cell Sci. 2002 Apr 1;115(Pt 7):1453-60 PMID: 11896193
  20. Dynein light chain regulates axonal trafficking and synaptic levels of Bassoon.
    J Cell Biol. 2009 Apr 20;185(2):341-55 PMID: 19380881
  21. Wnt signaling positions neuromuscular connectivity by inhibiting synapse formation in C. elegans.
    Cell. 2007 Aug 24;130(4):704-16 PMID: 17719547
  22. ik3-1/Cables is associated with Trap and Pctaire2.
    Biochem Biophys Res Commun. 2001 Sep 7;286(5):1045-50 PMID: 11527406
  23. Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity.
    J Neurosci. 2002 Apr 1;22(7):2590-7 PMID: 11923424
  24. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death.
    Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11173-8 PMID: 8855328
  25. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism.
    Nat Neurosci. 2007 Jan;10(1):67-76 PMID: 17143272
  26. Uncovering multiple axonal targeting pathways in hippocampal neurons.
    J Cell Biol. 2003 Sep 29;162(7):1317-28 PMID: 14517209
  27. NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein.
    Neuron. 2000 Dec;28(3):697-711 PMID: 11163260
  28. Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases.
    Neuron. 2006 Apr 6;50(1):13-8 PMID: 16600851
  29. Identification of an axonal determinant in the C-terminus of the sodium channel Na(v)1.2.
    EMBO J. 2001 Nov 1;20(21):5950-61 PMID: 11689435
  30. Lineage-specific regulation of cell cycle control gene expression during haematopoietic cell differentiation.
    Br J Haematol. 2000 Sep;110(3):663-73 PMID: 10997979
  31. UNC-6/netrin and its receptor UNC-5 locally exclude presynaptic components from dendrites.
    Nature. 2008 Oct 2;455(7213):669-73 PMID: 18776887
  32. A role for cyclin-dependent kinase(s) in the modulation of fast anterograde axonal transport: effects defined by olomoucine and the APC tumor suppressor protein.
    J Neurosci. 1998 Oct 1;18(19):7717-26 PMID: 9742142
  33. The somatodendritic endosomal regulator NEEP21 facilitates axonal targeting of L1/NgCAM.
    J Cell Biol. 2008 Feb 25;180(4):827-42 PMID: 18299352
  34. A Drosophila kinesin required for synaptic bouton formation and synaptic vesicle transport.
    Nat Neurosci. 2007 Aug;10(8):980-9 PMID: 17643120
  35. Clathrin adaptor AP-1 complex excludes multiple postsynaptic receptors from axons in C. elegans.
    Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1632-7 PMID: 19164532
  36. The regulation of tau phosphorylation by PCTAIRE 3: implications for the pathogenesis of Alzheimer's disease.
    Neurobiol Dis. 2006 Aug;23(2):398-408 PMID: 16766195
  37. Syntabulin-kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly.
    J Neurosci. 2007 Jul 4;27(27):7284-96 PMID: 17611281
  38. Dense core vesicle dynamics in Caenorhabditis elegans neurons and the role of kinesin UNC-104.
    Traffic. 2004 Jul;5(7):544-59 PMID: 15180830
  39. Expression of the positive regulator of cell cycle progression, cyclin D3, is induced during differentiation of myoblasts into quiescent myotubes.
    Oncogene. 1995 Jan 5;10(1):159-66 PMID: 7824268
  40. The structure of the nervous system of the nematode Caenorhabditis elegans.
    Philos Trans R Soc Lond B Biol Sci. 1986 Nov 12;314(1165):1-340 PMID: 22462104
  41. Pctaire1 interacts with p35 and is a novel substrate for Cdk5/p35.
    J Biol Chem. 2002 Aug 30;277(35):31988-93 PMID: 12084709
  42. A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons.
    EMBO J. 2004 Jun 2;23(11):2235-45 PMID: 15152189
  43. The role of selective transport in neuronal protein sorting.
    Neuron. 2000 May;26(2):465-72 PMID: 10839364
  44. A brain-specific activator of cyclin-dependent kinase 5.
    Nature. 1994 Sep 29;371(6496):423-6 PMID: 8090222
  45. Neuronal polarity and trafficking.
    Neuron. 2003 Oct 9;40(2):277-95 PMID: 14556709
  46. A novel disruption of cortical development in p35(-/-) mice distinct from reeler.
    J Comp Neurol. 1998 Jun 15;395(4):510-22 PMID: 9619503
  47. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport.
    Science. 2000 Jun 9;288(5472):1796-802 PMID: 10846156
  48. Two distinct mechanisms target membrane proteins to the axonal surface.
    Neuron. 2003 Feb 20;37(4):611-24 PMID: 12597859
  49. Precursor of cdk5 activator, the 23 kDa subunit of tau protein kinase II: its sequence and developmental change in brain.
    FEBS Lett. 1994 Nov 21;355(1):35-40 PMID: 7957957
  50. Cdk5 in neuroskeletal dynamics.
    Neurosignals. 2003 Sep-Oct;12(4-5):239-51 PMID: 14673211
  51. Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility.
    EMBO J. 2002 Feb 1;21(3):281-93 PMID: 11823421
  52. The structure of the ventral nerve cord of Caenorhabditis elegans.
    Philos Trans R Soc Lond B Biol Sci. 1976 Aug 10;275(938):327-48 PMID: 8806
  53. Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans.
    Cell. 1991 May 31;65(5):837-47 PMID: 1710172
  54. Characterization of brain PCTAIRE-1 kinase immunoreactivity and its interactions with p11 and 14-3-3 proteins.
    Eur J Biochem. 1998 Oct 1;257(1):112-20 PMID: 9799109
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2010.04.011
Published
2010-05-28
Pages
846-58
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3168554
Subset
IM
Grants
NINDS NIH HHS · R01 NS048392 · United States
Howard Hughes Medical Institute · United States
NINDS NIH HHS · R01 NS034307 · United States
NINDS NIH HHS · R01 NS048392-07 · United States
NINDS NIH HHS · R37 NS048392 · United States
NINDS NIH HHS · R01 NS048392-08 · United States
Corrections
CommentIn
PMID: 20692613
External Links
PubMed source DOI: 10.1016/j.cell.2010.04.011 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2