Wild type microglia arrest pathology in a mouse model of Rett syndrome
By Noël C. Derecki, James C. Cronk, Zhenjie Lu, Eric Xu, S. Abbott, P. Guyenet, Jonathan Kipnis. Nature, 2012
614 citations recorded by the source corpus.
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. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. 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.
Subfields: Genetics, Neurology, Physiology
View Paper: https://www.semanticscholar.org/paper/023486f96abbf893406f46e00727a4502c66bc47
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Citations in the corpus
- Origin and differentiation of microglia (2013, background): “For example, bone marrow transplantation of mouse models for metachromatic leukodystrophy (Biffi et al., 2004), the obsessive compulsive disorder trichotillomania (Chen et al., 2010), and Rett syndrome (Derecki et al., 2012) has been shown to ameliorate disease symptoms.”
- Microglia: Dynamic Mediators of Synapse Development and Plasticity (2015, background): “Mecp2 KO Rett Syndrome-like phenotype, rescued by bone marrow transplant from WT mice [49]”
- Microglia: new roles for the synaptic stripper. (2013, neutral): “Thus, constitutive microglial phagocytic activity appears to be essential for the development or maintenance of neuronal circuitry (Derecki et al., 2012).”
- MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system (2013, neutral): “We have not yet had the opportunity to analyze the relationships between gene expression, 5mC and 5hmC in other glial cell types that have been shown recently to play important roles in mouse models of RTT (Derecki et al., 2012; Lioy et al., 2012).”
- Microglia promote learning-dependent synapse formation through BDNF (2013, background): “…have also been associated with deletion or loss-offunction mutations in a number of genes expressed in microglia, including the fractalkine receptor CX3CR1, methyl CpG binding protein 2 (Mecp2), and homeobox protein HoxB8 (Chen et al., 2010; Derecki et al., 2012; Paolicelli et al., 2011).”