Adult Neural Function Requires MeCP2

Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Science (Impact Factor: 33.61). 06/2011; 333(6039):186. DOI: 10.1126/science.1206593
Source: PubMed


Rett syndrome (RTT) is a postnatal neurological disorder caused by mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2 (MeCP2). The onset of RTT symptoms during early life together with findings suggesting neurodevelopmental abnormalities in RTT and mouse models of RTT raised the question of whether maintaining MeCP2 function exclusively during early life might protect against disease. We show by using an inducible model of RTT that deletion of Mecp2 in adult mice recapitulates the germline knock-out phenotype, underscoring the ongoing role of MeCP2 in adult neurological function. Moreover, unlike the effects of other epigenetic instructions programmed during early life, the effects of early MeCP2 function are lost soon after its deletion. These findings suggest that therapies for RTT must be maintained throughout life.

7 Reads
    • "Accordingly, many studies have shown that Mecp2 null hippocampal slices are characterized by significant deficits in synaptic transmission (Asaka et al. 2006; Zhang et al. 2008), as well as in synaptic plasticity (Della Sala and Pizzorusso 2014). Interestingly, ablation of Mecp2 in adulthood results in defects of neuronal functions resembling those displayed by animals constitutively missing Mecp2 (Gemelli et al. 2006; Fyffe et al. 2008; McGraw et al. 2011; Cheval et al. 2012; Nguyen et al. 2012). Altogether, these conditional animal models indicate that MeCP2 must play a role in the maintenance of brain functionality at post-natal ages. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MeCP2 is associated with several neurological disorders; of which, Rett syndrome undoubtedly represents the most frequent. Its molecular roles, however, are still unclear, and data from animal models often describe adult, symptomatic stages, while MeCP2 functions during embryonic development remain elusive. We describe the pattern and timing of Mecp2 expression in the embryonic neocortex highlighting its low but consistent expression in virtually all cells and show the unexpected occurrence of transcriptional defects in the Mecp2 null samples at a stage largely preceding the onset of overt symptoms. Through the deregulated expression of ionic channels and glutamatergic receptors, the lack of Mecp2 during early neuronal maturation leads to the reduction in the neuronal responsiveness to stimuli. We suggest that such features concur to morphological alterations that begin affecting Mecp2 null neurons around the perinatal age and become evident later in adulthood. We indicate MeCP2 as a key modulator of the transcriptional mechanisms regulating cerebral cortex development. Neurological phenotypes of MECP2 patients could thus be the cumulative result of different adverse events that are already present at stages when no obvious signs of the pathology are evident and are worsened by later impairments affecting the central nervous system during maturation and maintenance of its functionality. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    Cerebral Cortex 05/2015; DOI:10.1093/cercor/bhv078 · 8.67 Impact Factor
  • Source
    • "In addition to sleep, breathing and musculoskeletal abnormalities resembling those of Rett syndrome, many Mecp2 mutant mice display aberrant behaviors characteristic of cognitive and emotional disturbances [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38]. Thus, the quantity, composition , and distribution of Mecp2 in early brain development and in the adult [39] [40] are critical for normal brain functioning [41]. Indeed , mutation of MECP2 causes severe and widespread alterations in brain cellular and molecular physiology [38,42–46]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rett syndrome is a Pervasive Developmental Disorder (PDD) associated with de novo mutations of the methyl CpG-binding protein 2 (MECP2) gene. Mecp2 functions as a transcription factor that regulating the expression of hundreds of genes. Identification of the role of Mecp2 in specific neurodevelopmental symptoms remains an important research aim. We previously demonstrated that male mice possessing a truncation mutation in Mecp2 are hyper-social. We predicted that reduced fear or anxiety might underlie this enhanced affiliation. In order to probe risk assessment and anxiety-like behavior, we compared Mecp2 truncation mutants to their wild-type littermates in the elevated plus maze and elevated zero maze. Additionally, subjects were administered the mouse defense test battery to evaluate unconditioned fear- and panic-like behavior to a graded set of threat scenarios and a predator stimulus. Mutant mice showed no significant changes in anxiety-like behavior. Yet, they displayed hyper-reactive escape and defensive behaviors to an animate predatory threat stimulus. Notably, mutant mice engaged in exaggerated active defense responding to threat stimuli at nearly all phases of the fear battery. These results reveal abnormalities in emotion regulation in Mecp2 mutants particularly in response to ecologically relevant threats. This hyper-responsivity suggests that transcriptional targets of Mecp2 are critical to emotion regulation. Moreover, we suggest that detailed analysis of defensive behavior and aggression with ethologically relevant tasks provides an avenue to interrogate gene-behavior mechanisms neurodevelopmental and other psychiatric conditions. Copyright © 2015. Published by Elsevier Inc.
    Physiology & Behavior 03/2015; 146. DOI:10.1016/j.physbeh.2015.03.035 · 2.98 Impact Factor
  • Source
    • "The majority of RTT individuals carry loss-of-function mutations in MECP2, the gene encoding methyl CpG-binding protein 2 (MeCP2), a global transcriptional regulator that binds to methylated CpG sites in promoter regions of DNA (Amir et al., 1999; Chahrour et al., 2008). Emerging evidence indicates that RTT results from a deficit in synaptic maturation in the brain, and that MeCP2 plays a critical role in neuronal and synaptic maturation and pruning during development (Cohen et al., 2003; Calfa et al., 2011b), as well as in the function of established neuronal networks in adulthood (McGraw et al., 2011). Pyramidal neurons in the cortex and hippocampus of RTT individuals have dendrites with atypical morphology (Belichenko et al., 1994; Armstrong et al., 1995; Chapleau et al., 2009a; Figure 1A). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Spines are small cytoplasmic extensions of dendrites that form the postsynaptic compartment of the majority of excitatory synapses in the mammalian brain. Alterations in the numerical density, size, and shape of dendritic spines have been correlated with neuronal dysfunction in several neurological and neurodevelopmental disorders associated with intellectual disability, including Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder associated with intellectual disability that is caused by loss of function mutations in the transcriptional regulator methyl CpG-binding protein 2 (MECP2). Here, we review the evidence demonstrating that principal neurons in RTT individuals and Mecp2-based experimental models exhibit alterations in the number and morphology of dendritic spines. We also discuss the exciting possibility that signaling pathways downstream of brain-derived neurotrophic factor (BDNF), which is transcriptionally regulated by MeCP2, offer promising therapeutic options for modulating dendritic spine development and plasticity in RTT and other MECP2-associated neurodevelopmental disorders.
    Frontiers in Neuroanatomy 09/2014; 8:97. DOI:10.3389/fnana.2014.00097 · 3.54 Impact Factor
Show more


7 Reads
Available from