Article

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

ABSTRACT

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.

Full-text preview

Available from: ncbi.nlm.nih.gov
  • Source
    • "One study used an inducible knockout approach to delete Mecp2 by crossing a floxed Mecp2 allele mice with a tamoxifen-inducible Cre-ER expressing allele in adult mice (P60 or older) following normal development[109]. This late-deletion of Mecp2 recapitulated key germline knockout phenotypes including abnormal gait, hind-limb clasping, motor abnormalities, impaired nesting ability, and impaired learning and memory, further underscoring the importance of Mecp2 in adult neurological function[109]. Interestingly, this adult deletion recapitulated an epigenetic memory clock, suggesting a mechanism that extends—or is independent from—its early global genetic regulation[110]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rett Syndrome was long considered to be simply a disorder of postnatal development, with phenotypes that manifest only late in development and into adulthood. A variety of recent evidence demonstrates that the phenotypes of Rett Syndrome are present at the earliest stages of brain development, including developmental stages that define neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. These phenotypes arise from the pleotropic effects of MeCP2, which is expressed very early in neuronal progenitors and continues to be expressed into adulthood. The effects of MeCP2 are mediated by diverse signaling, transcriptional, and epigenetic mechanisms. Attempts to reverse the effects of Rett Syndrome need to take into account the developmental dynamics and temporal impact of MeCP2 loss.
    Full-text · Article · Jan 2016
    • "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: journals.permissions@oup.com.
    No preview · Article · May 2015 · Cerebral Cortex
  • 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.
    Full-text · Article · Mar 2015 · Physiology & Behavior
Show more