Abstract
BackgroundRett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for the gene expression and chromatin regulator, methyl-CpG binding protein 2. Although the behavioral phenotype appears to be primarily due to neuronal Mecp2 deficiency in mice, other cell types, including astrocytes and oligodendrocytes, also appear to contribute to some aspects of the RTT phenotype. In addition, microglia may also play a role. However, the effect of Mecp2 deficiency in microglia on RTT pathogenesis is controversial.MethodsIn the current study, we applied whole transcriptome analysis using RNA-seq to gain insight into molecular pathways in microglia that might be dysregulated during the transition, in female mice heterozygous for an Mecp2-null allele (Mecp2+/−; Het), from the pre-phenotypic (5 weeks) to the phenotypic phases (24 weeks).ResultsWe found a significant overlap in differentially expressed genes (DEGs) with genes involved in regulating the extracellular matrix, and those that are activated or inhibited when macrophages and microglia are stimulated towards the M1 and M2 activation states. However, the M1- and M2-associated genes were different in the 5- and 24-week samples. In addition, a substantial decrease in the expression of nine members of the heat shock protein (HSP) family was found in the 5-week samples, but not at 24 weeks.ConclusionsThese findings suggest that microglia from pre-phenotypic and phenotypic female mice are activated in a manner different from controls and that pre-phenotypic female mice may have alterations in their capacity to response to heat stress and other stressors that function through the HSP pathway.
Highlights
Rett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development
The findings, do not address whether altered expression of M1- and M2-associated genes is a primary event or secondary to neuronal dysfunction that is triggering microglial activation. These findings are again consistent with some of the findings described by Cronk et al, who showed that Mecp2 deficiency leads to dysregulation of inflammatory responses in microglia and macrophage [56]
Voineagu et al showed that the transcriptome changes they observed in the Autism spectrum disorders (ASD) brains converge with genome wide association study (GWAS) data, which are enriched for neuronal genes, in particular genes coding for synaptic proteins; immune changes have a less pronounced genetic component, suggesting that the differential expression found in ASD is secondary [58]
Summary
Rett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for the gene expression and chromatin regulator, methyl-CpG binding protein 2. Rett syndrome (RTT) is characterized by a progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is found in ~1/ 10,000–1/15,000 female births and is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for methyl-CpG binding protein 2 (MeCP2) [1]. Severe loss of function mutations are usually male-lethal, hypomorphic MeCP2 variants have been found in males with intellectual disability and behavioral deficits [6, 7].
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