Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Previous data have shown that MECP2 RNA is present in all mouse and human tissues tested, but the timing of expression and regional distribution have not been explored. We investigated the spatial and temporal distribution of the MeCP2 protein during mouse and human development. We found that in the adult mouse, MeCP2 is high in the brain, lung and spleen, lower in heart and kidney, and barely detectable in liver, stomach and small intestine. There was no obvious correlation between protein levels and RNA levels, suggesting that translation may be post-transcriptionally regulated by tissue-specific factors. The timing of MeCP2 expression in mouse and human correlated with the maturation of the central nervous system, with the ontogenetically older structures such as the spinal cord and brainstem becoming positive before newer structures such as the hippocampus and cerebral cortex. In the cortex, MeCP2 first appeared in the Cajal-Retzius cells, then in the neurons of the deeper, more mature cortical layers, and finally in the neurons of the more superficial layers. The MeCP2 protein was eventually present in a majority of neurons but was absent from glial cells. Our data suggest that MeCP2 may become abundant only once a neuron has reached a certain degree of maturity, and that this may explain some aspects of the RTT phenotype.

MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome

“…Such a targeting principle ensures proper spatiotemporal MeCP2 binding and likely contributes to transcriptional regulation. In the adult brain, when MeCP2 levels are significantly increased (11,17), we observe a distinct trend toward increased binding to misregulated genes RT-PCR analysis of isolated DNA from MeCP2-ChIP in adult and juvenile mouse hypothalamus using primers for mouse major satellite DNA and Bdnf. Each bar represents SEM; n = 3 or 4; *P < 0.05; n.s., not significant by paired, one-tailed Student's t test.…”

“…We reasoned that there might be binding cues for MeCP2 besides mCG in the mature nervous system when MeCP2 levels are much higher (11,17). Indeed, unique peaks of MeCP2 binding were observed in the adult mouse brain in areas of lower mCG that correspond to elevated local mCH density ( Fig.…”

“…Other studies have observed that MeCP2 binds to nonspecific DNA elements via its A/T hooks and basic and disordered protein domains, as well as to mCH, although the functional relevance of these interactions has not been explored (12)(13)(14)(15)(16). Given that MeCP2 levels rise in mammalian neurons for some time after birth (11,17) and approach those of the histone-octamer in the adult mouse brain (11), its differential binding to other DNA elements besides mCG is expected but has not yet been defined experimentally at high resolution. Moreover, the functional relevance of MeCP2 binding to non-CG methylated DNA has not been addressed.…”

Rett syndrome: new clinical and molecular insights

“…62 It is also worth noting that the observation that the features of RTT correlate with the timing of synapse development has lead to the most recent hypothesis that MeCP2 may be responsible for controlling the expression of genes, which control the development and maintenance of synapses, although this remains to be proven. 63,64 …”

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

“…Previous research has hypothesized that the normal development and function of the central nervous system is dependent on the methylation of cytosines [7,8,9,10]. Thus, DNA-methyltransferases (DNMTs) and methyl-CpG-binding protein 2 (MeCP2) are highly expressed in developing brains but decreases later in life [10,11]. Mutations in MECP2 are involved in the neurodevelopmental disorder Rett syndrome, as well as in some cases of mental retardation and autism [7,9,12,13].…”