MeCP2 encodes a methyl-CpG-binding protein that plays a critical role in repressing gene expression, mutations of which lead to Rett syndrome and autism.
Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively.
Expression of normal MeCP2 in either CamKII or Eno2 distribution was unable to prevent the appearance of most of the phenotypes of the RTT mouse models.
Notably, patient neural progenitor cells had 9.6-fold downregulated expression of IGFBP3, whose brain expression is affected by MECP2, aberrant in Rett syndrome.
These data provide additional evidence of variable expression in the Rett disorder phenotype and suggest MeCP2 testing may be warranted for females presenting with autistic disorder.
Surprisingly, overexpression of wt MECP2 also increased BDNF levels, while overexpression of RTT-associated MECP2 mutants failed to affect BDNF levels.
We discovered in the 5'-UTR (untranslated region) of MECP2 mRNA a highly conserved G-quadruplex which overlapped a known deletion in Rett syndrome patients with decreased levels of MeCP2 protein.
It is the cluster of functionally defective nerve cells lacking fully functional MeCP2 generated by inactivation of normal MECP2 allele that causes the wide spectrum of RTT symptoms.
Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome.
Decreased dendritic arborization is common to RS and autism, leading to further research on similarities in pathogenesis, including MeCP2 protein levels in autistic brains and MeCP2 effects on genes connected to autism, like DLX5 and genes on 15q11-13 region.
Their analysis showed that homeostatic regulation of MeCP2 gene is necessary for normal CNS functioning and that multiple complex pathways involving different neuronal and glial cell types are disrupted in RTT models.
Specifically, although MeCP2 is known to act as a transcriptional repressor, analyses of the RTT brain at steady-state conditions detected numerous differentially expressed genes, while the changes in transcript levels were mostly subtle.
Retrospective review of the medical records of 284 girls and women with RTT to determine serum 25-(OH)D and parathyroid hormone levels, nutritional status, dietary sources of vitamin D, exposure to anticonvulsants, degree of mobility, and MECP2 status.
Our findings suggest that selective activation of cholinergic MeCP2 is sufficient to reverse the locomotor impairment and increased anxiety-like behaviors at least in early symptomatic stage, supporting future development of RTT therapies associated with cholinergic system.
Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT.
In this review, we will highlight recent findings that have expanded our knowledge of MeCP2's functions, and we will discuss how epigenetic regulation, chromatin organization and circuit dynamics may contribute to the postnatal onset of Rett syndrome.
CDKL5 is a serine/threonine kinase whose involvement in Rett syndrome can be inferred by its ability to directly bind and mediate phosphorylation of MeCP2.
In Mecp2-null rats, abnormalities in breathing patterns were apparent in both decerebrate rats and awake animals, suggesting that RTT-type breathing abnormalities take place in the brainstem without forebrain input.