Wild-type microglia arrest pathology in a mouse model of Rett syndrome (original) (raw)

Nature volume 484, pages 105–109 (2012)Cite this article

Subjects

Abstract

Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein1,2,3,4,5. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction6. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned _Mecp2_-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm cre on an _Mecp2_-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type _Mecp2_-expressing microglia within the context of an _Mecp2_-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2+/− females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Van den Veyver, I. B. & Zoghbi, H. Y. Mutations in the gene encoding methyl-CpG-binding protein 2 cause Rett syndrome. Brain Dev. 23 (suppl. 1). S147–S151 (2001)
    Article Google Scholar
  2. Van den Veyver, I. B. & Zoghbi, H. Y. Genetic basis of Rett syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 8, 82–86 (2002)
    Article Google Scholar
  3. Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999)
    Article CAS Google Scholar
  4. Guy, J., Hendrich, B., Holmes, M., Martin, J. E. & Bird, A. A mouse _Mecp2_-null mutation causes neurological symptoms that mimic Rett syndrome. Nature Genet. 27, 322–326 (2001)
    Article CAS Google Scholar
  5. Nan, X. & Bird, A. The biological functions of the methyl-CpG-binding protein MeCP2 and its implication in Rett syndrome. Brain Dev. 23 (suppl. 1). S32–S37 (2001)
    Article Google Scholar
  6. Luikenhuis, S., Giacometti, E., Beard, C. F. & Jaenisch, R. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc. Natl Acad. Sci. USA 101, 6033–6038 (2004)
    Article ADS CAS Google Scholar
  7. Ballas, N., Lioy, D. T., Grunseich, C. & Mandel, G. Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nature Neurosci. 12, 311–317 (2009)
    Article CAS Google Scholar
  8. Maezawa, I., Swanberg, S., Harvey, D., LaSalle, J. M. & Jin, L. W. Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. J. Neurosci. 29, 5051–5061 (2009)
    Article CAS Google Scholar
  9. Lioy, D. T. et al. A role for glia in the progression of Rett’s syndrome. Nature 475, 497–500 (2011)
    Article CAS Google Scholar
  10. Maezawa, I. & Jin, L. W. Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J. Neurosci. 30, 5346–5356 (2010)
    Article CAS Google Scholar
  11. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010)
    Article ADS CAS Google Scholar
  12. Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neurosci. 10, 1538–1543 (2007)
    Article CAS Google Scholar
  13. Mildner, A. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nature Neurosci. 10, 1544–1553 (2007)
    Article CAS Google Scholar
  14. Boissonneault, V. et al. Powerful beneficial effects of macrophage colony-stimulating factor on β-amyloid deposition and cognitive impairment in Alzheimer’s disease. Brain 132, 1078–1092 (2009)
    Article Google Scholar
  15. Chen, S. K. et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775–785 (2010)
    Article CAS Google Scholar
  16. Hoogerbrugge, P. M. et al. Donor-derived cells in the central nervous system of twitcher mice after bone marrow transplantation. Science 239, 1035–1038 (1988)
    Article ADS CAS Google Scholar
  17. Simard, A. R., Soulet, D., Gowing, G., Julien, J. P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49, 489–502 (2006)
    Article CAS Google Scholar
  18. Shechter, R. et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6, e1000113 (2009)
    Article Google Scholar
  19. Chen, R. Z., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nature Genet. 27, 327–331 (2001)
    Article CAS Google Scholar
  20. Tropea, D. et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc. Natl Acad. Sci. USA 106, 2029–2034 (2009)
    Article ADS CAS Google Scholar
  21. Willemen, H. L. et al. Microglial/macrophage GRK2 determines duration of peripheral IL-1β-induced hyperalgesia: contribution of spinal cord CX3CR1, p38 and IL-1 signaling. Pain 150, 550–560 (2010)
    Article CAS Google Scholar
  22. Nijboer, C. H. et al. Cell-specific roles of GRK2 in onset and severity of hypoxic-ischemic brain damage in neonatal mice. Brain Behav. Immun. 24, 420–426 (2010)
    Article CAS Google Scholar
  23. Cho, I. H. et al. Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death. Brain 131, 3019–3033 (2008)
    Article Google Scholar
  24. Lu, Z. et al. Phagocytic activity of neuronal progenitors regulates adult neurogenesis. Nature Cell Biol. 13, 1076–1083 (2011)
    Article CAS Google Scholar
  25. Zhang, X. et al. A minimally invasive, translational biomarker of ketamine-induced neuronal death in rats: microPET imaging using 18F-annexin V. Toxicol. Sci. 111, 355–361 (2009)
    Article CAS Google Scholar
  26. Oldfors, A. et al. Rett syndrome: cerebellar pathology. Pediatr. Neurol. 6, 310–314 (1990)
    Article CAS Google Scholar
  27. McGraw, C. M., Samaco, R. C. & Zoghbi, H. Y. Adult neural function requires MeCP2. Science 333, 186 (2011)
    Article ADS CAS Google Scholar
  28. Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007)
    Article ADS CAS Google Scholar
  29. Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007)
    Article ADS CAS Google Scholar
  30. Drorbaugh, J. E. & Fenn, W. O. A barometric method for measuring ventilation in newborn infants. Pediatrics 16, 81–87 (1955)
    CAS PubMed Google Scholar

Download references

Acknowledgements

We thank S. Smith for editing the manuscript. We thank the members of the Kipnis laboratory as well as the members of the University of Virginia Neuroscience Department for their comments during multiple discussions of this work. We also thank S. Feldman for injection of neonatal mice, I. Smirnov for tail vein injections, and B. Tomlin and J. Jones for their animal care. N.C.D. is a recipient of a Hartwell Foundation post-doctoral fellowship. This work was primarily supported by a grant from the Rett Syndrome Research Trust (to J.K.) and in part by HD056293 and AG034113 (to J.K).

Author information

Authors and Affiliations

  1. Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, 22908, Virginia, USA
    Noël C. Derecki, James C. Cronk, Zhenjie Lu, Eric Xu & Jonathan Kipnis
  2. Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia, 22908, USA
    Noël C. Derecki, James C. Cronk & Jonathan Kipnis
  3. Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia, 22908, USA
    James C. Cronk & Jonathan Kipnis
  4. Undergraduate School of Arts and Sciences, University of Virginia, Charlottesville, Virginia, 22908, USA
    Eric Xu
  5. Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, Virginia, 22908, USA
    Stephen B. G. Abbott & Patrice G. Guyenet

Authors

  1. Noël C. Derecki
    You can also search for this author inPubMed Google Scholar
  2. James C. Cronk
    You can also search for this author inPubMed Google Scholar
  3. Zhenjie Lu
    You can also search for this author inPubMed Google Scholar
  4. Eric Xu
    You can also search for this author inPubMed Google Scholar
  5. Stephen B. G. Abbott
    You can also search for this author inPubMed Google Scholar
  6. Patrice G. Guyenet
    You can also search for this author inPubMed Google Scholar
  7. Jonathan Kipnis
    You can also search for this author inPubMed Google Scholar

Contributions

N.C.D. performed most of the experiments, analysed the data and prepared it for presentation, and contributed to experimental design and manuscript writing. J.C.C. performed the experiments with phagocytic activity of microglia in vivo and assisted with additional immunohistochemistry experiments along with data analysis and presentation, and contributed to experimental design and manuscript editing. Z.L. assisted with in vitro phagocytic activity experiments. E.X. assisted with animal behaviour scoring. S.B.G.A. assisted with plethysmography experiments and data analysis. P.G.G. assisted with plethysmography experimental design, data analysis and presentation of plethysmography-related data, and contributed to manuscript editing. J.K. designed the study, assisted with data analysis and presentation, and wrote the manuscript.

Corresponding author

Correspondence toJonathan Kipnis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-6. (PDF 576 kb)

Supplementary Movie 1

Representative wild type and Mecp2 −/y mice at ~7 weeks of age. Notice reduced size and activity of Mecp2 −/y littermate. Representative appearance, tremors and clasping are shown in Mecp2 −/y at 60 days of age. (MOV 17028 kb)

Supplementary Movie 2

Representative transplanted mice (wild-type → Mecp2 −/y and wild-type → wild-type) are shown at 18 weeks of age (14 weeks post bone marrow transplantation). Note improved appearance, activity, body size, and lack of visible tremors in wild-type → Mecp2 −/y mice. (MOV 10604 kb)

Supplementary Movie 3

Representative movie of wild-type → Mecp2 −/y mouse at 40 weeks of age (4- to 5-fold increase in lifespan). (MOV 9627 kb)

Supplementary Movie 4

Genetic approach: Mecp2 lox–stop mice were bred to Lysm Cre mice and their progeny ( Mecp2 lox–stop /yLysm Cre mice) are Mecp2 -null mice that express wild-type Mecp2 protein in myeloid cells (including microglia). Representative movie of these mice is shown. Note the body size and activity at 23 weeks of age. (MOV 18028 kb)

PowerPoint slides

Rights and permissions

About this article

Cite this article

Derecki, N., Cronk, J., Lu, Z. et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome.Nature 484, 105–109 (2012). https://doi.org/10.1038/nature10907

Download citation

Editorial Summary

Marrow implants in Rett syndrome

The X-linked autism spectrum disorder known as Rett syndrome is predominantly linked to mutations in the MECP2 gene. It is typically associated with neuronal dysfunction, almost exclusively in girls, but new evidence suggests that restoring MECP2 function in other cell types may also arrest disease development. Here, the authors show in a mouse model that transplanting bone marrow from wild-type mice into mice lacking Mecp2 results in an invasion of donor-derived microglial cells into the brain, accompanied by increased lifespan and reduced signs of disease, including improved breathing and locomotion. The donor cells expressed normal MECP2 and high levels of the neurotrophic factor IGF-1. These results point to a crucial role for microglia in Rett syndrome, and open the possibility that bone-marrow implants might be of therapeutic benefit.

Associated content