Expression Pattern of the Rett Syndrome Gene MeCP2 in Primate Prefrontal Cortex

Akbarian, Schahram; Chen, Richard Z.; Gribnau, Joost; Rasmussen, Theodore P.; Fong, Hiu‐fai; Jaenisch, Rudolf; Jones, Edward G.

doi:10.1006/nbdi.2001.0420

Cited by 109 publications

(73 citation statements)

References 23 publications

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“…MeCP2 is spatially and developmentally regulated, and is characterized by heterogeneous expression in subpopulations of neurons in the brain. The timing of MeCP2 expression correlates with the maturation of the central nervous system (47,48), and recent reports suggest that MeCP2 may be involved in synaptic plasticity (49). Finally, transgenic mouse models have demonstrated that either underexpression or overexpression of MeCP2 are detrimental to cognitive development indicating that levels of MeCP2 in the central nervous system are tightly regulated and crucial for neuronal function (16,17).…”

Section: Discussionmentioning

confidence: 99%

“…However, Chahrour et al (39) recently demonstrated that MeCP2 could activate and repress the transcription of a large number of genes. MeCP2 is expressed in most tissues and cell types with the highest expression levels detected in the brain, where it is present primarily in neurons (46,47). MeCP2 is spatially and developmentally regulated, and is characterized by heterogeneous expression in subpopulations of neurons in the brain.…”

Section: Discussionmentioning

confidence: 99%

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Chromosome 21-derived MicroRNAs Provide an Etiological Basis for Aberrant Protein Expression in Human Down Syndrome Brains

Kuhn

Nuovo

Terry

et al. 2010

Journal of Biological Chemistry

100

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Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. Bioinformatic annotation has established that human chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA target pairs that may play a role, in part, in mediating the DS phenotype. We demonstrate by luciferase/target mRNA 3-untranslated region reporter assays, and gain-and lossof-function experiments that miR-155 and -802 can regulate the expression of the predicted mRNA target, the methyl-CpG-binding protein (MeCP2). We also demonstrate that MeCP2 is underexpressed in DS brain specimens isolated from either humans or mice. We further demonstrate that, as a consequence of attenuated MeCP2 expression, transcriptionally activated and silenced MeCP2 target genes, CREB1/Creb1 and MEF2C/Mef2c, are also aberrantly expressed in these DS brain specimens. Finally, in vivo silencing of endogenous miR-155 or -802, by antagomir intraventricular injection, resulted in the normalization of MeCP2 and MeCP2 target gene expression. Taken together, these results suggest that improper repression of MeCP2, secondary to trisomic overexpression of Hsa21-derived miRNAs, may contribute, in part, to the abnormalities in the neurochemistry observed in the brains of DS individuals. Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS.The presence of three copies of all, or part, of human chromosome 21 (Hsa21) 2 results in the constellation of physiologic traits known as Down syndrome (DS) or Trisomy 21 (1).With an incidence of approximately one in 750 live births, DS is the most frequently survivable congenital chromosomal abnormality (2, 3). The phenotypes of DS are complex and variable; they include cognitive impairment, congenital heart defects, craniofacial abnormalities, gastrointestinal anomalies, leukemia, and Alzheimer disease (1-3). Experimental studies utilizing tissues derived from individuals with DS have confirmed that expression of trisomic genes is increased by ϳ50% (i.e. consistent with gene dosage) (4 -6). Recent bioinformatic annotation has established that Hsa21 harbors more than 500 genes (7, 8), including five miRNA genes (miR-99a, let-7c, miR125b-2, miR-155, and miR-802). miRNAs are a family of small, ϳ21-nucleotide long, nonprotein-coding RNAs that have emerged as key post-transcriptional regulators of gene expression (9 -11). miRNAs are processed from precursor molecules (pri-miRNAs), which are either transcribed from independent miRNA genes or are portions of introns of protein-coding RNA polymerase II transcripts. Following their processing, miRNAs are assembled into ribonucleoprotein complexes called microribonucleoproteins (miRNPs) or miRNA-...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chromosome 21-derived MicroRNAs Provide an Etiological Basis for Aberrant Protein Expression in Human Down Syndrome Brains

Kuhn

Nuovo

Terry

et al. 2010

Journal of Biological Chemistry

100

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“…MBD1 resembles MeCP2 because both are chromosome-bound proteins that repress transcription in a HDAC-dependent manner. In the brain, both methyl-binding proteins are expressed in neurons but not in differentiated glial cells (Akbarian et al, 2001;Zhao et al, 2003). We found a much higher HDAC2 expression in the various brain areas examined compared with HDAC1 expression, suggesting that the former deacetylase enzyme plays a major role in neuronal gene silencing.…”

Section: Discussionmentioning

confidence: 70%

Fluoxetine and Cocaine Induce the Epigenetic Factors MeCP2 and MBD1 in Adult Rat Brain

Cassel¹,

Carouge²,

Gensburger³

et al. 2006

Mol Pharmacol

176

133

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Once bound to methylated CpG sites, methyl-CpG-binding protein 2 (MeCP2) is thought to silence transcription of downstream genes by recruiting a histone deacetylase (HDAC). Mutations within the MeCP2 gene have been found to cause Rett syndrome, a disorder of arrested neuronal development. Using immunohistochemistry, we found that Mecp2, as well as the methyl-CpG-binding protein MBD1, were significantly induced in normal adult rat brain after repeated injections of fluoxetine or cocaine for 10 days (one injection per day). Mecp2 was not induced by repeated injections of 1-(2-bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl)piperazine (GBR-12909) or nortriptyline. Together, the data indicate that the serotonergic system is predominantly involved. Using real-time reverse transcription-polymerase chain reaction experiments, MBD1 mRNA and both Mecp2_e1 and Mecp2_e2 transcripts were found to be induced by fluoxetine. Induction of the methylbinding proteins was accompanied with enhanced HDAC2 labeling intensity and mRNA synthesis in response to fluoxetine. In tandem, acetylated forms of histone H3 were found to be decreased. The effect was characterized in three serotonin projection areas, the caudate-putamen, the frontal cortex, and the dentate gyrus subregion of hippocampus. Our data highlight GABAergic neurons as major target cells expressing Mecp2 in response to the serotonin-elevating agents and suggest that serotonin signaling enhances gene silencing in postmitotic neurons.

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“…In mouse, the protein localizes to highly methylated pericentromeric heterochromatin (5). Although MeCP2 is found in most tissues and cell types, highest expression levels are detected in the brain, where it is primarily present in neurons but not in glia (5)(6)(7). The timing of Mecp2 expression correlates with the maturation of the CNS (5,8), and recent reports suggest that MeCP2 may be involved in the formation of synaptic contacts (9).…”

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confidence: 99%