Expression of MeCP2 in olfactory receptor neurons is developmentally regulated and occurs before synaptogenesis (original) (raw)

MeCP2 is required for activity-dependent refinement of olfactory circuits

Molecular and Cellular Neuroscience, 2014

Methyl CpG binding protein 2 (MeCP2) is a structural chromosomal protein involved in the regulation of gene expression. Alterations in the levels of MeCP2 have been related to neurodevelopmental disorders. Studies in mouse models of MeCP2 deficiency have demonstrated that this protein is important for neuronal maturation, neurite complexity, synaptogenesis, and synaptic plasticity. However, the mechanisms by which MeCP2 dysfunction leads to neurodevelopmental defects, and the role of activity, remain unclear, as most studies examine the adult nervous system, which may obfuscate the primary consequences of MeCP2 mutation. We hypothesize that MeCP2 plays a role during the formation and activity-driven maturation of neural circuits at early postnatal stages. To test this hypothesis, we use the olfactory system as a neurodevelopmental model. This system undergoes postnatal neurogenesis; axons from olfactory neurons form highly stereotyped projections to higher-order neurons, facilitating the detection of possible defects in the establishment of connectivity. In vivo olfactory stimulation paradigms were

Lack of MeCP2 leads to region-specific increase of doublecortin in the olfactory system

Brain Structure and Function, 2019

The protein doublecortin is mainly expressed in migrating neuroblasts and immature neurons. The Xlinked gene MECP2, associated to several neurodevelopmental disorders such as Rett Syndrome, encodes the protein methyl-CpG-binding protein 2 (MeCP2), a regulatory protein that has been implicated in neuronal maturation and refinement of olfactory circuits. Here we explored doublecortin immunoreactivity in the brain of young-adult female Mecp2-heterozygous and male Mecp2-null mice and their wild-type littermates. The distribution of doublecortin-immunorective somata in neurogenic brain regions was consistent with previous reports in rodents, and no qualitative differences were found between genotypes or sexes. Quantitatively, we found a significant increase in doublecortin cell density in in the piriform cortex of Mecp2-null males as compared to WT littermates. A similar increase was seen in a newly-identified population of doublecortin cells in the olfactory tubercle. In these olfactory structures, however, the percentage of doublecortin immature neurons that also expressed NeuN was not different between genotypes. By contrast, we found no significant differences between genotypes in doublecortinimmunorectivity in the olfactory bulbs. Nonetheless, in the periglomerular layer of Mecp2-null males we observed a specific decrease of immature neurons co-expressing doublecortin and NeuN. Overall, no differences were evident between Mecp2-heterozygous and WT females. Also, no differences could be detected between genotypes in the density of doublecortin-immunoreactive cells in the hippocampus or striatum of either males or females. Our results suggest that MeCP2 is involved in neuronal maturation in a region-dependent manner.

Temporal and regional differences in the olfactory proteome as a consequence of MeCP2 deficiency

Proceedings of the National Academy of Sciences, 2004

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the gene encoding MeCP2. By binding to methylated CpG dinucleotide promoter regions, MeCP2 acts as a transcriptional repressor, predicting that its absence might result in widespread aberrant gene transcription, leading to the RTT phenotype. Considering this potentially broad action of MeCP2 on expression and the complexity of the brain, especially during development, we approached the consequences of MeCP2 deficiency in a mouse model by using a temporal and regional proteomic strategy. We used the olfactory system (olfactory epithelium and bulb) because its attributes make it an excellent developmental model system. We find evidence of temporal and regional proteomic pattern differences between WT and MeCP2-deficient mice. It was possible to segregate these changes in protein expression into five biological function groups: cytoskeleton arrangement, chromatin modeling, energy metabolism, cell signaling, and neuroprotection. By combining the proteomic results with the RNA levels of the identified proteins, we show that protein expression changes are the consequence of differences in mRNA level or posttranslational modifications. We conclude that brain regions and ages must be carefully considered when investigating MeCP2 deficiency, and that not only transcription should be taken into account as a source for these changes, but posttranslational protein modifications as well.