Wild-type microglia do not reverse pathology in mouse models of Rett syndrome

Jieqi Wang, Jan Eike Wegener, Teng-Wei Huang, Smitha Sripathy, Hector De Jesus-Cortes, Pin Xu, Stephanie Tran, Whitney Knobbe, Vid Leko, Jeremiah Britt, Ruth Starwalt, Latisha McDaniel, Chris S. Ward, Diana Parra, Benjamin Newcomb, Uyen Lao, Cynthia Nourigat, David A. Flowers, Sean Cullen, Nikolas L. Jorstad, Yue Yang, Lena Glaskova, Sébastien Vigneau, Julia Kozlitina, Michael J. Yetman, Joanna L. Jankowsky, Sybille D. Reichardt, Holger M. Reichardt, Jutta Gärtner, Marisa S. Bartolomei, Min Fang, Keith Loeb, C. Dirk Keene, Irwin Bernstein, Margaret Goodell, Daniel J. Brat, Peter Huppke (), Jeffrey L. Neul (), Antonio Bedalov () and Andrew A. Pieper ()
Additional contact information
Jieqi Wang: University of Texas Southwestern Medical Center
Jan Eike Wegener: University Medical Center Göttingen
Teng-Wei Huang: Jan and Dan Duncan Neurological Research Institute (Texas Children’s Hospital), Baylor College of Medicine
Smitha Sripathy: Fred Hutchinson Cancer Research Center
Hector De Jesus-Cortes: Graduate Program of Neuroscience, University of Texas Southwestern Medical Center
Pin Xu: Graduate Program of Neuroscience, University of Texas Southwestern Medical Center
Stephanie Tran: University of Texas Southwestern Medical Center
Whitney Knobbe: University of Texas Southwestern Medical Center
Vid Leko: Fred Hutchinson Cancer Research Center
Jeremiah Britt: University of Iowa Carver College of Medicine
Ruth Starwalt: University of Texas Southwestern Medical Center
Latisha McDaniel: University of Iowa Carver College of Medicine
Chris S. Ward: Jan and Dan Duncan Neurological Research Institute (Texas Children’s Hospital), Baylor College of Medicine
Diana Parra: Jan and Dan Duncan Neurological Research Institute (Texas Children’s Hospital), Baylor College of Medicine
Benjamin Newcomb: Fred Hutchinson Cancer Research Center
Uyen Lao: Fred Hutchinson Cancer Research Center
Cynthia Nourigat: Fred Hutchinson Cancer Research Center
David A. Flowers: Fred Hutchinson Cancer Research Center
Sean Cullen: Program in Developmental Biology, Baylor College of Medicine
Nikolas L. Jorstad: University of Washington School of Medicine
Yue Yang: University of Washington School of Medicine
Lena Glaskova: University of Washington School of Medicine
Sébastien Vigneau: Perelman School of Medicine at the University of Pennsylvania
Julia Kozlitina: University of Texas Southwestern Medical Center
Michael J. Yetman: Baylor College of Medicine
Joanna L. Jankowsky: Baylor College of Medicine
Sybille D. Reichardt: Institute for Cellular and Molecular Immunology; University of Göttingen Medical School
Holger M. Reichardt: Institute for Cellular and Molecular Immunology; University of Göttingen Medical School
Jutta Gärtner: University Medical Center Göttingen
Marisa S. Bartolomei: Perelman School of Medicine at the University of Pennsylvania
Min Fang: Fred Hutchinson Cancer Research Center
Keith Loeb: Fred Hutchinson Cancer Research Center
C. Dirk Keene: University of Washington School of Medicine
Irwin Bernstein: Fred Hutchinson Cancer Research Center
Margaret Goodell: Program in Developmental Biology, Baylor College of Medicine
Daniel J. Brat: Emory University School of Medicine
Peter Huppke: University Medical Center Göttingen
Jeffrey L. Neul: Jan and Dan Duncan Neurological Research Institute (Texas Children’s Hospital), Baylor College of Medicine
Antonio Bedalov: Fred Hutchinson Cancer Research Center
Andrew A. Pieper: University of Iowa Carver College of Medicine

Nature, 2015, vol. 521, issue 7552, E1-E4

Abstract: Abstract arising from N. C. Derecki et al. Nature 484, 105–109 (2012); doi:10.1038/nature10907 Rett syndrome is a severe neurodevelopmental disorder caused by mutations in the X chromosomal gene MECP2 (ref. 1), and its treatment so far is symptomatic. Mecp2 disruption in mice phenocopies major features of the syndrome2 that can be reversed after Mecp2 re-expression3. Recently, Derecki et al.4 reported that transplantation of wild-type bone marrow into lethally irradiated Mecp2-null (Mecp2tm1.1Jae/y) mice prevented neurological decline and early death by restoring microglial phagocytic activity against apoptotic targets4, and clinical trials of bone marrow transplantation (BMT) for patients with Rett syndrome have thus been initiated5. We aimed to replicate and extend the BMT experiments in three different Rett syndrome mouse models, but found that despite robust microglial engraftment, BMT from wild-type donors did not prevent early death or ameliorate neurological deficits. Furthermore, early and specific Mecp2 genetic expression in microglia did not rescue Mecp2-deficient mice.

Date: 2015
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DOI: 10.1038/nature14444

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