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Wild-type microglia arrest pathology in a mouse model of Rett syndrome

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 Lysmcre 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.

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Figure 1: Wild-type bone marrow transplantation (BMT) at P28 arrests disease progression in Mecp2 −/y mice.
Figure 2: Bone marrow transplantation effects on general appearance, breathing and locomotion of Mecp2 −/y and Mecp2 +/− mice.
Figure 3: Brain parenchymal engraftment of cells after bone marrow transplantation is required to arrest Rett syndrome.
Figure 4: Microglial phagocytic activity is necessary for their beneficial effect in Mecp2 −/y mouse brains.

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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).

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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.

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Correspondence to Jonathan Kipnis.

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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−/yand 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: Mecp2lox–stop mice were bred to LysmCre mice and their progeny ( Mecp2lox–stop/yLysmCre 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)

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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

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