Journal Article

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

Derecki, Noël C., Xu, Eric, Abbott, Stephen B. G., Kipnis, Jonathan, Lu, Zhenjie, Cronk, James C., Guyenet, Patrice G.

2012

Overview

Transplanting bone marrow from wild-type mice into MECP2-lacking mice results in wild-type microglial engraftment, extends lifespan and reduces symptoms of disease such as breathing and locomotor abnormalities, implicating microglia in the pathophysiology of Rett syndrome. 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. 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 protein 1 , 2 , 3 , 4 , 5 . Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction 6 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/2596/1953 / 692/699/375 / 692/700/139/422 / Animals / Annexin A5 - administration & dosage / Annexin A5 - metabolism / Annexin A5 - pharmacology / Apoptosis - drug effects / Arrests / Autism / Biological and medical sciences / Body weight / Body Weight - physiology / Bone marrow / Bone Marrow Transplantation / Brain - cytology / Development and progression / Disease Models, Animal / Disease Progression / Female / Fundamental and applied biological sciences. Psychology / Genetic aspects / Genotype & phenotype / Humanities and Social Sciences / Insulin-Like Growth Factor I - metabolism / Insulin-like growth factors / Irradiation / letter / Locomotion / Locomotor activity / Male / Methyl-CpG-Binding Protein 2 - deficiency / Methyl-CpG-Binding Protein 2 - genetics / Methyl-CpG-Binding Protein 2 - metabolism / Mice / Mice, Inbred C57BL / Microglia - cytology / Microglia - pathology / Microglia - physiology / Microglia - transplantation / multidisciplinary / Pathology / Phagocytosis - drug effects / Phosphatidylserines - metabolism / Respiration - drug effects / Rett syndrome / Rett Syndrome - genetics / Rett Syndrome - pathology / Rett Syndrome - physiopathology / Rett Syndrome - therapy / Rodents / Rotarod Performance Test / Science / Science (multidisciplinary) / Transplants & implants / Vertebrates: nervous system and sense organs