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Cited by 46Genetics and Neurodevelopmental DisordersGenetic and Kidney Cyst DiseasesCystic Fibrosis Research Advances

MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders

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Frasca, Angelisa, Spiombi, Eleonora, Palmieri, Michela, Albizzati, Elena, Valente, Maria Maddalena, Bergo, Anna, Leva, Barbara, Kilstrup‐Nielsen, Charlotte +4 more·2020·EMBO Molecular Medicine
DOI 10.15252/emmm.201910270PMC PMC7278541
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Abstract

Mutations in MECP2 cause several neurological disorders of which Rett syndrome (RTT) represents the best‐defined condition. Although mainly working as a transcriptional repressor, MeCP2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscure. Besides being mainly localized in the nucleus, MeCP2 associates with the centrosome, an organelle from which primary cilia originate. Primary cilia function as “sensory antennae” protruding from most cells, and a link between primary cilia and mental illness has recently been reported. We herein demonstrate that MeCP2 deficiency affects ciliogenesis in cultured cells, including neurons and RTT fibroblasts, and in the mouse brain. Consequently, the cilium‐related Sonic Hedgehog pathway, which is essential for brain development and functioning, is impaired. Microtubule instability participates in these phenotypes that can be rescued by HDAC6 inhibition together with the recovery of RTT‐related neuronal defects. Our data indicate defects of primary cilium as a novel pathogenic mechanism that by contributing to the clinical features of RTT might impact on proper cerebellum/brain development and functioning, thus providing a novel therapeutic target.

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  • Notable perturbation-specific gene ontology terms include ribosome assembly (SETD5), mitochondrion organization (FOXP1), lipid homoeostasis (IRF2BPL), autophagosome maturation (KAT2B), and cilium development (MECP2).

    “Some notable examples include the gene ontology terms ribosome assembly (SETD5 perturbation)36, mitochondrion organization (FOXP1 perturbation)37, lipid homoeostasis (IRF2BPL perturbation)38, autophagosome maturation (KAT2B perturbation)39 and cilium development (MECP2 perturbation)40.”

    From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [40]

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References 68 · Cited by 46

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  1. Allemang‐Grand R, Ellegood J, Spencer Noakes L, Ruston J, Justice M, Nieman BJ, Lerch JP (2017) Neuroanatomy in mouse models of Rett syndrome is related to the severity of Mecp2 mutation and behavioral phenotypes. Mol Autism 8: 1– 13 28670438 PMC5485541
  2. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X‐linked MECP2, encoding methyl‐CpG‐binding protein 2. Nat Genet 23: 185– 188 10508514
  3. Bedogni F, Rossi RL, Galli F, Cobolli Gigli C, Gandaglia A, Kilstrup‐Nielsen C, Landsberger N (2014) Rett syndrome and the urge of novel approaches to study MeCP2 functions and mechanisms of action. Neurosci Biobehav Rev 46: 187– 201 24594195
  4. Bedogni F, Cobolli Gigli C, Pozzi D, Rossi RL, Scaramuzza L, Rossetti G, Pagani M, Kilstrup‐Nielsen C, Matteoli M, Landsberger N (2016) Defects during Mecp2 null embryonic cortex development precede the onset of overt neurological symptoms. Cereb Cortex 26: 2517– 2529 25979088
  5. Bellini E, Pavesi G, Barbiero I, Bergo A, Chandola C, Nawaz MS, Rusconi L, Stefanelli G, Strollo M, Valente MM et al (2014) MeCP2 post‐translational modifications: a mechanism to control its involvement in synaptic plasticity and homeostasis? Front Cell Neurosci 8: 1– 15 25165434 PMC4131190
  6. Bergo A, Strollo M, Gai M, Barbiero I, Stefanelli G, Sertic S, Cobolli Gigli C, Di Cunto F, Kilstrup‐Nielsen C, Landsberger N (2015) Methyl‐CpG binding protein 2 (MeCP2) localizes at the centrosome and is required for proper mitotic spindle organization. J Biol Chem 290 3223– 3237 25527496 PMC4318997
  7. Bishop G, Berbari NF, Lewis JS, Mykytyn K (2007) Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse. J Comp Neurol 505: 562– 571 17924533
  8. Chahrour M, Zoghbi HY (2007) The story of rett syndrome: from clinic to neurobiology. Neuron 56: 422– 437 17988628
  9. Cheng TL, Qiu Z (2014) MeCP2: multifaceted roles in gene regulation and neural development. Neurosci Bull 30: 601– 609 25082535 PMC5562630
  10. Clouaire T, Stancheva I (2008) Methyl‐CpG binding proteins: specialized transcriptional repressors or structural components of chromatin? Cell Mol Life Sci 65: 1509– 1522 18322651 PMC2873564
  11. Corrales JD, Blaess S, Mahoney EM, Joyner AL (2006) The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation. Development 133: 1811– 1821 16571625
  12. D'Annessa I, Gandaglia A, Brivio E, Stefanelli G, Frasca A, Landsberger N, Di Marino D (2018) Tyr120Asp mutation alters domain flexibility and dynamics of MeCP2 DNA binding domain leading to impaired DNA interaction: atomistic characterization of a Rett syndrome causing mutation. Biochim Biophys Acta Gen Subj 1862: 1180– 1189 29428602
  13. De Diego AS, Alonso Guerrero A, Martínez‐A C, Van Wely KHM (2014) Dido3‐dependent HDAC6 targeting controls cilium size. Nat Commun 5: 1– 11 PMC3973121 24667272
  14. De Smaele E, Fragomeli C, Ferretti E, Pelloni M, Po A, Canettieri G, Coni S, Di Marcotulli L, Greco A, Moretti M et al (2008) An integrated approach identifies Nhlh1 and Insm1 as sonic hedgehog‐regulated genes in developing cerebellum and medulloblastoma. Neoplasia 10: 89‐IN36 18231642 PMC2213903
  15. Delépine C, Nectoux J, Bahi‐Buisson N, Chelly J, Bienvenu T (2013) MeCP2 deficiency is associated with impaired microtubule stability. FEBS Lett 587: 245– 253 23238081
  16. Delépine C, Meziane H, Nectoux J, Opitz M, Smith AB, Ballatore C, Saillour Y, Bennaceur‐Griscelli A, Chang Q, Cunningham Williams E et al (2016) Altered microtubule dynamics and vesicular transport in mouse and human MeCP2‐deficient astrocytes. Hum Mol Genet 25: 146– 157 26604147 PMC4690499
  17. Ezeonwuka C, Rastegar M (2014) MeCP2‐related diseases and animal models. Diseases 2: 45– 70 28191346 PMC5298922
  18. Falcón‐Urrutia P, Carrasco CM, Lois P, Palma V (2015) Shh signaling through the primary cilium modulates rat oligodendrocyte differentiation. PLoS One 10: 1– 14 PMC4517900 26218245
  19. Forcioli‐Conti N, Est D, Bouloumi A, Dani C, Peraldi P (2016) The size of the primary cilium and acetylated tubulin are modulated during adipocyte differentiation: analysis of HDAC6 functions in these processes. Biochimie 124: 112– 123 26363102
  20. Gandaglia A, Brivio E, Carli S, Palmieri M, Bedogni F, Stefanelli G, Bergo A, Leva B, Cattaneo C, Pizzamiglio L et al (2018) A novel Mecp2 Y120D knock‐in model displays similar behavioral traits but distinct molecular features compared to the Mecp2 ‐null mouse implying precision medicine for the treatment of rett syndrome. Mol Neurobiol 56: 4838– 4854 30402709
  21. Ge X, Frank CL, Calderon de Anda F, Tsai L (2010) Hook3 interacts with PCM1 to regulate pericentriolar material assembly and the timing of neurogenesis. Neuron 65: 191– 203 20152126 PMC2902371
  22. Ghosh RP, Horowitz‐Scherer RA, Nikitina T, Shlyakhtenko LS, Woodcock CL (2010) MeCP2 binds cooperatively to its substrate and competes with histone H1 for chromatin binding sites. Mol Cell Biol 30: 4656– 4670 20679481 PMC2950531
  23. Goetz SC, Anderson KV (2010) The primary cilium: a signaling center during vertebrate development. Nat Rev Genet 11: 331– 344 20395968 PMC3121168
  24. Gold WA, Lacina TA, Cantrill LC, Christodoulou J (2015) MeCP2 deficiency is associated with reduced levels of tubulin acetylation and can be restored using HDAC6 inhibitors. J Mol Med 93: 63– 72 25209898
  25. Guadiana SM, Semple‐Rowland S, Daroszewski D, Madorsky I, Breunig JJ, Mykytyn K, Sarkisian MR (2013) Arborization of dendrites by developing neocortical neurons is dependent on primary cilia and type 3 Adenylyl Cyclase. J Neurosci 33: 2626– 2638 23392690 PMC6619186
  26. Hagberg B, Hanefeld F, Percy A, Skjeldal O (2002) An update on clinically applicable diagnostic criteria in Rett syndrome: comments to Rett syndrome clinical criteria consensus panel satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol 6: 293– 297 12378695
  27. Ip JP, Mellios N, Sur M (2018) Rett syndrome: insights into genetic, molecular and circuit mechanisms. Nat Rev Neurosci 19: 368– 382 29740174 PMC6402579
  28. Jones PL, Jan G, Veenstra C, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19: 187– 191 9620779
  29. Keeling J, Tsiokas L, Maskey D (2016) Cellular mechanisms of ciliary length control. Cells 5: 6 PMC4810091 26840332
  30. Kenney AM, Rowitch DH (2000) Sonic hedgehog promotes G1 cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 20: 9055– 9067 11074003 PMC86558
  31. Korobeynikov V, Deneka AY, Golemis EA, Program T, Chase F, Biology C, Federation R (2018) Mechanisms for non‐mitotic activation of Aurora‐A at cilia. Mechanisms 45: 37– 49 PMC5860652 28202658
  32. Kuijpers M, Hoogenraad CC (2011) Centrosomes, microtubules and neuronal development. Mol Cell Neurosci 48: 349– 358 21722732
  33. Landucci E, Brindisi M, Bianciardi L, Catania LM, Daga S, Croci S, Meloni I (2018) iPSC‐derived neurons profiling reveals GABAergic circuit disruption and acetylated α‐tubulin defect which improves after iHDAC6 treatment in Rett syndrome. Exp Cell Res 368: 225– 235 29730163 PMC9410763
  34. Mansini A, Pisarello MJL, Thelen MK, Cruz‐Reyes M, Peixoto E, Jin S, Howard BN, Trussoni CE, Gajdos GB, La Russo NF et al (2018) MiR‐433 and miR‐22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma. Hepatology, 68: 561– 573 29406621 PMC6078832
  35. Marley A, von Zastrow M (2012) A simple cell‐based assay reveals that diverse neuropsychiatric risk genes converge on primary cilia. PLoS One 7: e46647 23056384 PMC3463515
  36. Nan X, Hou J, Maclean A, Nasir J, Lafuente MJ, Shu X, Kriaucionis S, Bird A (2007) Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proc Natl Acad Sci 104: 2709– 2714 17296936 PMC1796997
  37. Novarino G, Akizu N, Gleeson JG (2011) Modeling human disease in humans: the ciliopathies. Cell 147: 70– 79 21962508 PMC3202432
  38. Pala R, Alomari N, Nauli SM (2017) Primary cilium‐dependent signaling mechanisms. Int J Mol Sci 18: E2272 29143784 PMC5713242
  39. Park SM, Jang HJ, Lee JH, Parlato R, Traiffort E (2019) Roles of primary cilia in the developing brain. Front Cell Neurosci 13: 1– 10 31139054 PMC6527876
  40. Ramocki MB, Tavyev YJ, Peters SU (2010) The MECP2 duplication syndrome. Am J Med Genet A 152A: 1079– 1088 20425814 PMC2861792
  41. van Reeuwijk J, Arts HH, Roepman R (2011) Scrutinizing ciliopathies by unraveling ciliary interaction networks. Hum Mol Genet 20: 149– 157 21862450
  42. Shiohama T, Levman J, Takahashi E (2019) Surface‐ and voxel‐based brain morphologic study in Rett and Rett‐like syndrome with MECP2 mutation. Int J Dev Neurosci 73: 83– 88 30690146 PMC6377336
  43. Skene PJ, Illingworth RS, Webb S, Kerr ARW, James KD, Turner DJ, Andrews R, Bird AP (2010) Neuronal MeCP2 is expressed at near histone‐octamer levels and globally alters the chromatin state. Mol Cell 37: 457– 468 20188665 PMC4338610
  44. Stearns T (2001) Centrosome duplication: a centriolar pas de deux. Cell 105: 417– 420 11371338
  45. Stefanelli G, Gandaglia A, Costa M, Cheema MS, Di Marino D, Barbiero I, Kilstrup‐Nielsen C, Ausio J, Landsberger N (2016) Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association. Sci Rep 6: 28295 27323888 PMC4915018
  46. Tsai PT, Rudolph S, Guo C, Ellegood J, Jennifer M, Schaeffer SM, Mogavero J, Lerch JP, Regehr W, Sahin M (2018) Sensitive periods for cerebellar‐mediated autistic‐like behaviours. Cell Rep 25: 357– 367 30304677 PMC6226056
  47. Vaillant C, Monard D (2009) SHH pathway and cerebellar development. Cerebellum 8: 291– 301 19224309
  48. Valente EM, Rosti RO, Gibbs E, Gleeson JG (2014) Primary cilia in neurodevelopmental disorders. Nat Rev Neurol 10: 27– 36 24296655 PMC3989897
  49. Ware SM, Aygun MG, Hildebrandt F (2011) Spectrum of clinical diseases caused by disorders of primary cilia. Proc Am Thorac Soc, 8: 444– 450 21926397 PMC3209578
  50. Wheway G, Nazlamova L, Hancock JT (2018) Signaling through the primary cilium. Front Cell Dev Biol 6: 1– 13 29473038 PMC5809511
  51. Xu X, Alan P, Pozzo‐miller L (2014) A selective histone deacetylase‐6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome. Front Cell Neurosci 8: 1– 9 24639629 PMC3945638
  52. Youn YH, Han YG (2018) Primary cilia in brain development and diseases. Am J Pathol 188: 11– 22 29030052 PMC5745523
  53. Young JI, Hong EP, Castle JC, Crespo‐Barreto J, Bowman AB, Rose MF, Kang D, Richman R, Johnson JM, Berget S et al (2005) Regulation of RNA splicing by the methylation‐dependent transcriptional repressor methyl‐CpG binding protein 2. Proc Natl Acad Sci, 102: 17551– 17558 16251272 PMC1266160
  54. Yu F, Ran J, Zhou J (2016) Ciliopathies: does HDAC6 represent a new therapeutic target? Trends Pharmacol Sci 37: 114– 119 26651415

Authors
Frasca, A., Spiombi, E., Palmieri, M., Albizzati, E., Valente, M. M., Bergo, A., Leva, B., Kilstrup‐Nielsen, C., Bianchi, F., Di Carlo, V., Di Cunto, F., & Landsberger, N.
Affiliations
  • University of Milan (IT)
  • IRCCS Ospedale San Raffaele (IT)
  • University of Insubria (IT)
  • Neuroscience Institute Cavalieri Ottolenghi (IT)
Corresponding author
Landsberger, Nicoletta
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2020-05-08
Volume
12
Issue
6
Pages
e10270-e10270
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.15252/emmm.201910270
PMC
PMC7278541
OpenAlex
W3021594944
Cited by
46
References
68
Citations by year
2026: 3 · 2025: 9 · 2024: 9 · 2023: 11 · 2022: 7 · 2021: 4 · 2020: 2 · 2019: 1
FWCI
3.66
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, cc-by)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IrInSubria (University of Insubria) (submittedVersion, other-oa)
Funders
ProRETT Ricerca
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
Keywords
MeCP2, Rett syndrome, ciliogenesis, primary cilia, centrosome, sonic hedgehog pathway, microtubule instability, HDAC6 inhibition, cerebellar development, brain development, transcriptional repressor
MeSH terms
Animals, Brain, Humans, Mutation, Rett Syndrome, Mice, Methyl-CpG-Binding Protein 2, Hedgehog Proteins

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