A role for glia in the progression of Rett’s syndrome
Open accessAbstract
Rett's syndrome (RTT) is an X-chromosome-linked autism spectrum disorder caused by loss of function of the transcription factor methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is expressed in most tissues, loss of MeCP2 expression results primarily in neurological symptoms. Earlier studies suggested the idea that RTT is due exclusively to loss of MeCP2 function in neurons. Although defective neurons clearly underlie the aberrant behaviours, we and others showed recently that the loss of MECP2 from glia negatively influences neurons in a non-cell-autonomous fashion. Here we show that in globally MeCP2-deficient mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged lifespan compared to globally null mice. Furthermore, restoration of MeCP2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter VGLUT1. Our study shows that glia, like neurons, are integral components of the neuropathology of RTT, and supports the targeting of glia as a strategy for improving the associated symptoms.
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Selective reactivation of Mecp2 expression in astrocytes of Mecp2 knock-out mice results in significant rescue of behavioral and neuronal phenotype.
“selective reactivation of Mecp2 expression in astrocytes of Mecp2 KO mice resulted in a significant rescue of both behavioral and neuronal phenotype”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Lioy et al., 2011
The passages on behavior and neuronal anatomy report improved behavioral measures and restored dendritic branching and other neuronal measures after astrocytic MeCP2 re-expression. However, the experiments used Mecp2Stop mice, not complete Mecp2 knockouts: the paper notes residual MeCP2 expression from the stop allele and distinguishes these mice from Mecp2-/y mice. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRe-introducing MeCP2 to astrocytes of Mecp2 null mice using GFAP-Cre improves symptoms and restores dendritic morphology.
“Moreover, deletion of MeCP2 from glial cells induces a RTT-like phenotype, and re-introducing MeCP2 to astrocytes of Mecp2 null mice using GFAP-Cre improves symptoms and restores dendritic morphology [193,194].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [193]
The paper reports that tamoxifen-induced MeCP2 re-expression using hGFAPcreT2 improved RTT-like symptoms and restored the number of apical dendritic branches (passages 2, 3, and 6). However, the rescue mice carried a Mecp2Stop allele, not a true null allele: the paper distinguishes them from Mecp2-/y mice and reports residual MeCP2 expression from the stop locus (passage 8). (LLM, conf=0.88)
Experimental — accuracy not yet measuredDeletion of MeCP2 from glial cells induces a RTT-like phenotype.
“Moreover, deletion of MeCP2 from glial cells induces a RTT-like phenotype, and re-introducing MeCP2 to astrocytes of Mecp2 null mice using GFAP-Cre improves symptoms and restores dendritic morphology [193,194].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [193]
Astrocytes supplement neuronal cholesterol through lipoprotein transfer.
“since astrocytes supplement neuronal cholesterol through lipoprotein transfer45,46.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [45]
The paper’s Abstract reports that restoring MeCP2 in astrocytes improves neuronal morphology and other Rett-like features in mice, but it does not describe cholesterol supplementation or lipoprotein transfer. Searches for cholesterol, lipoproteins, and astrocyte-to-neuron lipid transfer found no passage addressing that mechanism in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Cites
Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes
Foust, K. D., Nurre, E., Montgomery, C. L., Hernandez, A., Chan, C. M., & Kaspar, B. K. (2009) · Nature Biotechnology · doi:10.1038/nbt.1515 · Cited by 1,456 · see citing works
Self-citationDeficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice
Chen, R. Z., Akbarian, S., Tudor, M., & Jaenisch, R. (2001) · Nature Genetics · doi:10.1038/85906 · Cited by 1,275 · see citing works
Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes
Chao, H.-T., Chen, H., Samaco, R. C., Xue, M., Chahrour, M., Yoo, J., Neul, J. L., Gong, S., Lu, H.-C., Heintz, N., et al. (2010) · Nature · doi:10.1038/nature09582 · Cited by 1,168 · see citing works
Neuropathology of Rett syndrome
Armstrong, D. D. (2005) · Journal of Child Neurology · doi:10.1177/08830738050200082401 · Cited by 207 · see citing works
Hirrlinger, P. G., Scheller, A., Braun, C., Hirrlinger, J., & Kirchhoff, F. (2006) · Glia · doi:10.1002/glia.20342 · Cited by 200 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 29
- [1]Chahrour M Zoghbi HY Neuron 2007 56 422 37 17988628
- [2]Shahbazian MD Antalffy B Armstrong DL Zoghbi HY Hum. Mol. Genet 2002 11 115 11809720
- [3]Guy J Hendrich B Holmes M Martin JE Bird A Nat. Genet 2001 3 322 6 11242117
- [4]Chen RZ Akbarian S Tudor M Jaenisch R Nat. Genet 2001 3 327 31 11242118
- [5]Kishi N Macklis JD Mol. Cell Neurosci 2004 27 306 21 15519245
- [6]McGill BE Bundle SF Yaylaoglu MB Carson JP Thaller C Zoghbi HY PNAS 2006 103 18267 72 17108082 PMC1636379
- [7]Fyffe SL Neuron 2008 59 947 58 18817733 PMC2597031
- [8]Samaco RC PNAS 2009 106 21966 71 20007372 PMC2799790
- [9]Luikenhuis S Giacometti E Beard CF Jaenisch R PNAS 2004 101 6033 8 15069197 PMC395918
- [10]Chao HT Nature 2010 468 263 9 21068835 PMC3057962
- [11]Ballas N Lioy DT Grunseich C Mandel G Nat. Neurosci 2009 12 311 7 19234456 PMC3134296
- [12]Maezawa I Swanberg S Harvey D LaSalle JM Jin LW J. Neurosci 2009 29 5051 61 19386901 PMC3436907
- [13]Maezawa I Jin LW J. Neurosci 2010 30 5346 56 20392956 PMC5533099
- [14]Guy J Gan J Selfridge J Cobb S Bird A Science 2007 315 1143 7 17289941 PMC7610836
- [15]Hirrlinger PG Scheller A Braun C Hirrlinger J Kirchhoff F Glia 2006 54 11 20 16575885
- [16]Brenner M Kisseberth WC Su Y Besnard F Messing A J. Neurosci 1994 14 1030 7 8120611 PMC6577554
- [17]Chow L Zhang J Baker SJ Transgenic Res 2008 17 919 28 18483774 PMC2522290
- [18]Casper KB Jones K McCarthy KD Genesis 2007 45 292 9 17457931
- [19]Foust KD Nurre E Montgomery CL Hernandez A Chan CM Kaspar BK Nat. Biotechnol 2008 27 59 65 19098898 PMC2895694
- [20]Stearns NA Schaevitz LR Bowling H Nag N Berger UV Berger-Sweeney J Neurosci 2007 146 907 21 17383101
- [21]Pelka GJ Brain 2006 129 Pt. 887-98 16467389
- [22]Weese-Mayer DE Pediatr. Res 2006 60 443 9 16940240
- [23]Viemari J J. Neurosci 2005 25 11521 30 16354910 PMC6726028
- [24]Bauman ML Kemper TL Arin DM Neurol 1995 45 1581 6 7644058
- [25]Armstrong DD J. Child Neurol 2005 20 747 53 16225830
- [26]Chao HT Zoghbi HY Rosenmund C Neuron 2007 56 58 65 17920015 PMC2198899
- [27]Marchetto ML Cell 2010 143 527 39 21074045 PMC3003590
- [28]Ilieva H Polymenidou M Cleveland DW J. Cell Biol 2009 187 761 72 19951898 PMC2806318
- [29]Gemelli T Berton O Nelson ED Perrotti LI Jaenisch R Monteggia LM Biol. Psych 2006 59 468 76 16199017
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Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 5,508 · see citing works
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Mellén, M., Ayata, P., Dewell, S., Kriaucionis, S., & Heintz, N. (2012) · Cell · doi:10.1016/j.cell.2012.11.022 · Cited by 943 · see citing works
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de la Torre-Ubieta, L., Won, H., Stein, J. L., & Geschwind, D. H. (2016) · Nature Medicine · doi:10.1038/nm.4071 · Cited by 827 · see citing works
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Aguzzi, A., Barres, B. A., & Bennett, M. L. (2013) · Science · doi:10.1126/science.1227901 · Cited by 836 · see citing works
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Molofsky, A. V., Krenick, R., Ullian, E., Tsai, H.-H., Deneen, B., Richardson, W. D., Barres, B. A., & Rowitch, D. H. (2012) · Genes & Development · doi:10.1101/gad.188326.112 · Cited by 682 · see citing works
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Adamsky, A., Kol, A., Kreisel, T., Doron, A., Ozeri-Engelhard, N., Melcer, T., Refaeli, R., Horn, H., Regev, L., Groysman, M., et al. (2018) · Cell · doi:10.1016/j.cell.2018.05.002 · Cited by 631 · see citing works
Wild-type microglia arrest pathology in a mouse model of Rett syndrome
Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B. G., Guyenet, P. G., & Kipnis, J. (2012) · Nature · doi:10.1038/nature10907 · Cited by 607 · see citing works
Tay, T. L., Savage, J. C., Hui, C. W., Bisht, K., & Tremblay, M. (2017) · The Journal of Physiology · doi:10.1113/jp272134 · Cited by 562 · see citing works
The Indispensable Roles of Microglia and Astrocytes during Brain Development
Reemst, K., Noctor, S. C., Lucassen, P. J., & Hol, E. M. (2016) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2016.00566 · Cited by 516 · see citing works
Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders
Lee, E., Lee, J., & Kim, E. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.05.011 · Cited by 468 · see citing works
Microglia: actively surveying and shaping neuronal circuit structure and function
Wake, H., Moorhouse, A. J., Miyamoto, A., & Nabekura, J. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.11.007 · Cited by 448 · see citing works
Prada, I., Gabrielli, M., Turola, E., Iorio, A., D’Arrigo, G., Parolisi, R., De Luca, M., Pacifici, M., Bastoni, M., Lombardi, M., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-017-1803-x · Cited by 312 · see citing works
Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders
Sahin, M., & Sur, M. (2015) · Science · doi:10.1126/science.aab3897 · Cited by 295 · see citing works
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Goffin, D., Allen, M., Zhang, L., Amorim, M., Wang, I.-T. J., Reyes, A.-R. S., Mercado-Berton, A., Ong, C., Cohen, S., Hu, L., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.2997 · Cited by 226 · see citing works
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Buchovecky, C. M., Turley, S. D., Brown, H. M., Kyle, S. M., McDonald, J. G., Liu, B., Pieper, A. A., Huang, W., Katz, D. M., Russell, D. W., et al. (2013) · Nature Genetics · doi:10.1038/ng.2714 · Cited by 234 · see citing works
An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy
Millan, M. J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.015 · Cited by 229 · see citing works
Preclinical research in Rett syndrome: setting the foundation for translational success
Katz, D. M., Berger-Sweeney, J. E., Eubanks, J. H., Justice, M. J., Neul, J. L., Pozzo-Miller, L., Blue, M. E., Christian, D., Crawley, J. N., Giustetto, M., et al. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.011007 · Cited by 206 · see citing works
Rett syndrome: a neurological disorder with metabolic components
Kyle, S. M., Vashi, N., & Justice, M. J. (2018) · Open Biology · doi:10.1098/rsob.170216 · Cited by 213 · see citing works
Cronk, J. C., Derecki, N. C., Ji, E., Xu, Y., Lampano, A. E., Smirnov, I., Baker, W., Norris, G. T., Marin, I., Coddington, N., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.03.013 · Cited by 199 · see citing works
Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome
Robinson, L., Guy, J., McKay, L., Brockett, E., Spike, R. C., Selfridge, J., De Sousa, D., Merusi, C., Riedel, G., Bird, A., et al. (2012) · Brain · doi:10.1093/brain/aws096 · Cited by 157 · see citing works
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Kaiser, T., & Feng, G. (2015) · Nature Medicine · doi:10.1038/nm.3935 · Cited by 157 · see citing works
Schafer, D. P., Heller, C. T., Gunner, G., Heller, M., Gordon, C., Hammond, T., Wolf, Y., Jung, S., & Stevens, B. (2016) · eLife · doi:10.7554/elife.15224 · Cited by 147 · see citing works
MeCP2 modulates gene expression pathways in astrocytes
Yasui, D. H., Xu, H., Dunaway, K. W., LaSalle, J. M., Jin, L.-W., & Maezawa, I. (2013) · Molecular Autism · doi:10.1186/2040-2392-4-3 · Cited by 90 · see citing works
Pacheco, N. L., Heaven, M. R., Holt, L. M., Crossman, D. K., Boggio, K. J., Shaffer, S. A., Flint, D. L., & Olsen, M. L. (2017) · Molecular Autism · doi:10.1186/s13229-017-0174-4 · Cited by 90 · see citing works
Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice
Kishi, N., MacDonald, J. L., Ye, J., Molyneaux, B. J., Azim, E., & Macklis, J. D. (2016) · Nature Communications · doi:10.1038/ncomms10520 · Cited by 69 · see citing works
Lang, M., Wither, R. G., Brotchie, J. M., Wu, C., Zhang, L., & Eubanks, J. H. (2013) · Human Molecular Genetics · doi:10.1093/hmg/dds433 · Cited by 30 · see citing works
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Postogna, F. M., Giancroce, N., Cabasino, C., Biella, F., Roggero, O. M., Breccia, M., Morelli, L., Colombo, D., Arcari, A., Lunghi, G., et al. (2026) · doi:10.64898/2026.07.29.741426 · Cited by 1 · see citing works
“Consistently, selective reactivation of Mecp2 expression in astrocytes of Mecp2 KO mice resulted in a significant rescue of both behavioral and neuronal phenotype, highlighting astrocytes as important contributors to disease pathogenesis and potential therapeutic targets (Lioy et al., 2011).”
- Authors
- Lioy, D. T., Garg, S. K., Monaghan, C. E., Raber, J., Foust, K. D., Kaspar, B. K., Hirrlinger, P. G., Kirchhoff, F., Bissonnette, J. M., Ballas, N., & Mandel, G.
- Affiliations
- Oregon Health & Science University (US)
- Howard Hughes Medical Institute (US)
- Oregon National Primate Research Center (US)
- Nationwide Children's Hospital (US)
- Leipzig University (DE)
- Max Planck Institute of Experimental Medicine (DE)
- Stony Brook University (US)
- Corresponding author
- Mandel, Gail
- ORCID
- Venue
- Nature
- Published
- 2011-06-29
- Volume
- 475
- Issue
- 7357
- Pages
- 497-500
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3268776
- OpenAlex
- W2026751327
- Cited by
- 496
- References
- 5
- Citations by year
- 2026: 14 · 2025: 12 · 2024: 20 · 2023: 14 · 2022: 31 · 2021: 31 · 2020: 20 · 2019: 27 · 2018: 33 · 2017: 31 · 2016: 49 · 2015: 53 · 2014: 45 · 2013: 54 · 2012: 53
- FWCI
- 32.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Neurological Disorders and Stroke (P30NS061800)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD056503)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- MeCP2, glia, astrocytes, non-cell-autonomous effects, neuron-glia interactions, autism spectrum disorder, dendritic morphology, VGLUT1, glutamate transporters, locomotion, anxiety, respiratory abnormalities, lifespan, neuropathology
- MeSH terms
- Animals, Anxiety, Astrocytes, Behavior, Animal, Female, Gene Expression Regulation, Male, Mice, Inbred C57BL, Motor Activity, Neuroglia, Neurons, Rett Syndrome, Disease Progression, Vesicular Glutamate Transport Protein 1, Mice, Methyl-CpG-Binding Protein 2
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