Home LiteratureArticle Details
PMID: 22922712 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons.

Nature cell biology ·Vol. 14 ·No. 9 ·2012-09-00 ·Pages 911-23

Ricciardi S, Ungaro F, Hambrock M, Rademacher N, Stefanelli G, Brambilla D, Sessa A, Magagnotti C, Bachi A, Giarda E, Verpelli C, Kilstrup-Nielsen C, Sala C, Kalscheuer VM, Broccoli V

Abstract

Mutations of the cyclin-dependent kinase-like 5 (CDKL5) and netrin-G1 (NTNG1) genes cause a severe neurodevelopmental disorder with clinical features that are closely related to Rett syndrome, including intellectual disability, early-onset intractable epilepsy and autism. We report here that CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. To exert this role, CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95. Accordingly, phospho-mutant NGL-1 is unable to induce synaptic contacts whereas its phospho-mimetic form binds PSD95 more efficiently and partially rescues the CDKL5-specific spine defects. Interestingly, similarly to rodent neurons, iPSC-derived neurons from patients with CDKL5 mutations exhibit aberrant dendritic spines, thus suggesting a common function of CDKL5 in mice and humans.

MeSH Terms
Amino Acid Sequence Animals COS Cells Cell Adhesion/genetics,physiology Cells, Cultured Chlorocebus aethiops Dendritic Spines/metabolism,pathology Disks Large Homolog 4 Protein Excitatory Postsynaptic Potentials/genetics,physiology Female Glutamic Acid/metabolism HEK293 Cells Humans Intracellular Signaling Peptides and Proteins/genetics,metabolism Membrane Proteins/genetics,metabolism Mice Molecular Sequence Data Mutation Nerve Tissue Proteins/genetics,metabolism Neurons/metabolism,physiology Phosphorylation Protein Serine-Threonine Kinases/genetics,metabolism Receptors, Cell Surface/genetics,metabolism Rett Syndrome/genetics,metabolism,pathology Spine/metabolism,pathology Synapses/genetics,metabolism
Chemicals
DLG4 protein, human Disks Large Homolog 4 Protein Intracellular Signaling Peptides and Proteins LRRC4C protein, human Membrane Proteins Nerve Tissue Proteins Receptors, Cell Surface Glutamic Acid Protein Serine-Threonine Kinases CDKL5 protein, human
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Ricciardi Sara
Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
Ungaro Federica
Hambrock Melanie
Rademacher Nils
Stefanelli Gilda
Brambilla Dario
Sessa Alessandro
Magagnotti Cinzia
Bachi Angela
Giarda Elisa
Verpelli Chiara
Kilstrup-Nielsen Charlotte
Sala Carlo
Kalscheuer Vera M
Broccoli Vania
References (46)
46 references, click to expand
  1. Synaptic adhesion molecules and PSD-95.
    Prog Neurobiol. 2008 Mar;84(3):263-83 PMID: 18206289
  2. Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations.
    Neurosci Lett. 2008 Apr 25;435(3):194-7 PMID: 18384956
  3. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation.
    Am J Hum Genet. 2003 Jun;72(6):1401-11 PMID: 12736870
  4. Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation.
    J Biol Chem. 2011 Oct 21;286(42):36550-8 PMID: 21832092
  5. CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome.
    Hum Mol Genet. 2005 Jul 15;14(14):1935-46 PMID: 15917271
  6. The story of Rett syndrome: from clinic to neurobiology.
    Neuron. 2007 Nov 8;56(3):422-37 PMID: 17988628
  7. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.
    Nat Genet. 1999 Oct;23(2):185-8 PMID: 10508514
  8. Long-term culture and differentiation of CNS precursors derived from anterior human neural rosettes following exposure to ventralizing factors.
    Exp Cell Res. 2010 Apr 15;316(7):1148-58 PMID: 20171210
  9. Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and Rett-like features.
    Neurogenetics. 2011 May;12(2):165-7 PMID: 21318334
  10. Mechanisms of disease: neurogenetics of MeCP2 deficiency.
    Nat Clin Pract Neurol. 2006 Apr;2(4):212-21 PMID: 16932552
  11. Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation.
    J Biol Chem. 2006 Oct 20;281(42):32048-56 PMID: 16935860
  12. Trans-synaptic adhesion between NGL-3 and LAR regulates the formation of excitatory synapses.
    Nat Neurosci. 2009 Apr;12(4):428-37 PMID: 19252495
  13. Encephalopathy and bilateral cataract in a boy with an interstitial deletion of Xp22 comprising the CDKL5 and NHS genes.
    Am J Med Genet A. 2007 Feb 15;143(4):364-9 PMID: 17256798
  14. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
    Nature. 2012 Apr 04;485(7397):246-50 PMID: 22495309
  15. Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3).
    Hum Genet. 2009 Jun;125(5-6):581-90 PMID: 19296131
  16. CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail.
    J Biol Chem. 2008 Oct 31;283(44):30101-11 PMID: 18701457
  17. Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome.
    Eur J Hum Genet. 2005 Aug;13(8):921-7 PMID: 15870826
  18. Key clinical features to identify girls with CDKL5 mutations.
    Brain. 2008 Oct;131(Pt 10):2647-61 PMID: 18790821
  19. Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy.
    Epilepsia. 2010 Apr;51(4):647-54 PMID: 19780792
  20. NGL family PSD-95-interacting adhesion molecules regulate excitatory synapse formation.
    Nat Neurosci. 2006 Oct;9(10):1294-301 PMID: 16980967
  21. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.
    J Med Genet. 2006 Sep;43(9):729-34 PMID: 16611748
  22. Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region.
    Genomics. 1998 Aug 1;51(3):427-33 PMID: 9721213
  23. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation.
    Am J Hum Genet. 2004 Dec;75(6):1149-54 PMID: 15499549
  24. Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized.
    Nat Rev Genet. 2006 Jun;7(6):415-26 PMID: 16708070
  25. Dendritic spines: structure, dynamics and regulation.
    Nat Rev Neurosci. 2001 Dec;2(12):880-8 PMID: 11733795
  26. Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand.
    J Neurosci. 2004 Nov 10;24(45):10248-59 PMID: 15537897
  27. Characterization of the proteome, diseases and evolution of the human postsynaptic density.
    Nat Neurosci. 2011 Jan;14(1):19-21 PMID: 21170055
  28. CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms.
    J Med Genet. 2005 Feb;42(2):103-7 PMID: 15689447
  29. The postsynaptic density.
    Curr Biol. 2009 Sep 15;19(17):R723-4 PMID: 19906568
  30. CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling.
    J Neurosci. 2010 Sep 22;30(38):12777-86 PMID: 20861382
  31. Binding of the inward rectifier K+ channel Kir 2.3 to PSD-95 is regulated by protein kinase A phosphorylation.
    Neuron. 1996 Oct;17(4):759-67 PMID: 8893032
  32. Integration of biochemical signalling in spines.
    Nat Rev Neurosci. 2005 Jun;6(6):423-34 PMID: 15928715
  33. Female human iPSCs retain an inactive X chromosome.
    Cell Stem Cell. 2010 Sep 3;7(3):329-42 PMID: 20727844
  34. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.
    Am J Hum Genet. 2004 Dec;75(6):1079-93 PMID: 15492925
  35. CDKL5 alterations lead to early epileptic encephalopathy in both genders.
    Epilepsia. 2011 Oct;52(10):1835-42 PMID: 21770923
  36. Neurotransmitters drive combinatorial multistate postsynaptic density networks.
    Sci Signal. 2009 Apr 28;2(68):ra19 PMID: 19401593
  37. A tissue-specific atlas of mouse protein phosphorylation and expression.
    Cell. 2010 Dec 23;143(7):1174-89 PMID: 21183079
  38. Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy.
    J Med Genet. 2008 Mar;45(3):172-8 PMID: 17993579
  39. The netrin-G1 ligand NGL-1 promotes the outgrowth of thalamocortical axons.
    Nat Neurosci. 2003 Dec;6(12):1270-6 PMID: 14595443
  40. The NGL family of leucine-rich repeat-containing synaptic adhesion molecules.
    Mol Cell Neurosci. 2009 Sep;42(1):1-10 PMID: 19467332
  41. CDKL5 truncation due to a t(X;2)(p22.1;p25.3) in a girl with X-linked infantile spasm syndrome.
    Clin Genet. 2010 Jan;77(1):92-6 PMID: 19807736
  42. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells.
    Cell. 2010 Nov 12;143(4):527-39 PMID: 21074045
  43. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein.
    Nature. 1998 Dec 3;396(6710):433-9 PMID: 9853749
  44. Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome.
    Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14169-74 PMID: 21807996
  45. Serine phosphorylation of ephrinB2 regulates trafficking of synaptic AMPA receptors.
    Nat Neurosci. 2008 Sep;11(9):1035-43 PMID: 19160501
  46. CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery.
    Hum Mol Genet. 2009 Dec 1;18(23):4590-602 PMID: 19740913
Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb2566
Published
2012-09-00
Epub
2012-00-26
Pages
911-23
Language
English
Region
England
NLM ID
100890575
PMCID
PMC6485419
Subset
IM
Grants
Telethon · GGP09196 · Italy
Telethon · GGP11110 · Italy
External Links
PubMed source DOI: 10.1038/ncb2566 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: [email protected]

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