The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells

Abstract

Mutations in the MeCP2 gene cause Rett syndrome, a neurologic condition affecting primarily young girls. To gain insight into the normal function of MeCP2, we examined its temporal and spatial expression patterns, and immunoreactive prevalence, during late embryonic and perinatal brain development. MeCP2 mRNA was detected in most regions of the developing rat brain by the late embryonic stage. Regions displaying the strongest mRNA expression include the hippocampus, cortex, and cerebellum, and moderate expression was observed in most other brain regions. At the protein level, MeCP2 was strongly expressed in adult forebrain neurons, but was not detected in astrocytes. The nonubiquitous expression of MeCP2 was also observed in the embryonic cortex, as about one-third of acutely dissociated embryonic day 14 neuroepithelial cells failed to stain with MeCP2. To test whether MeCP2 expression correlates with neuronal differentiation, colocalization of MeCP2 expression with either the precursor cell marker nestin or the young neuronal marker beta-III tubulin was examined in the same acutely dissociated cortical cells. Although strong MeCP2 expression was detected in approximately 75% of beta-III tubulin-positive cells, only about 25% of nestin-positive precursor cells were MeCP2 positive. Further support for a correlation of MeCP2 expression with cell differentiation was observed in culture, where Western blot analysis during the in vitro differentiation of PC12, NG108-15, and SH-SY5Y cells revealed that MeCP2 levels increased as the cells acquired a more differentiated phenotype. This increase was associated with differentiation, as MeCP2 expression levels did not vary within different phases of the cell cycle. Taken together, these data support a role for MeCP2 in the establishment and/or maintenance of neuronal maturity.

A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations

“…On the other hand, promotion of RPC proliferation in mice by transgenic expression of B-catenin (39) or caspase-9 (40) knockout results in expansion of cortical surface area and gyral folding, but has no apparent effect on thickness. While MECP2 activity is usually associated with the newly mature neuron, neuronal precursors do stain for MECP2 (41). The role of MECP2 in RPC proliferation is worthy of examination in light of our finding that MECP2 variants associate with cortical surface area, but not thickness.…”

Epigenetic mechanisms regulating fate specification of neural stem cells

“…Mutations in MeCP2 have been linked to the neurological disorder Rett syndrome (Shahbazian et al 2002a;Kriaucionis & Bird 2003). Rett syndrome patients are characterized by normal development until 1 year of age, followed by a rapid deterioration involving loss of acquired speech and motor skills, microcephaly, seizures, autism, ataxia, intermittent hyperventilation and characteristic stereotypic movements (Nomura & Segawa 1990;Guy et al 2001;Jung et al 2003;Segawa & Nomura 2005). Mice deficient for MBD1 showed decreased neurogenesis, defects in spatial learning and a reduction in long-term potentiation in the dentate gyrus of the hippocampus (Zhao et al 2003).…”

Inhibition of DNA Methylation and Methyl-CpG-Binding Protein 2 Suppresses RPE Transdifferentiation: Relevance to Proliferative Vitreoretinopathy

“…Alterations in DNA methylation status are associated with many biological processes, including wound healing and fibrosis, [29][30][31][32] DNA repair, 33,34 cell cycle regulation, [35][36] inflammatory/stress response, 37,38 apoptosis, and tumorigenesis. 39 DNA methylation at the 5 position of cytosine within CpG dinucleotides epigenetically controls gene expression and maintains genome integrity.…”

“…Methyl-CpG-binding protein 2 (MeCP2) is the prototypic methyl-CpG-binding protein. [30][31][32] Methyl-CpG-binding proteins bind to methylated DNA through a conserved methyl-CpG-binding domain where they typically repress gene expression. [30][31][32] 5-aza-2 0 -deoxycytidine (5-AZA-dC) is a potent inhibitor of DNA methylation that has been used to study the relevance of DNA methylation to EMT.…”