Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice

Abstract

Mecp2 is an X-linked gene encoding a nuclear protein that binds specifically to methylated DNA (ref. 1) and functions as a general transcriptional repressor by associating with chromatin-remodeling complexes. Mecp2 is expressed at high levels in the postnatal brain, indicating that methylation-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system. Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that Mecp2-deficient mice exhibit phenotypes that resemble some of the symptoms of RTT patients. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. Mutant brains showed substantial reduction in both weight and neuronal cell size, but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day (E) 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the CNS rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. Our results indicate that the role of Mecp2 is not restricted to the immature brain, but becomes critical in mature neurons. Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome.

Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

“…Consistent with published data Chen et al, 2001;Dubois et al, 2006), we observed near-complete recombination in the cortex, and complete recombination in the cerebellum (Fig. 1C).…”

Advances in behavioral genetics: mouse models of autism

“…[72][73][74] The Mecp2-null mouse, a genetic model for the disease, shows overtly normal development for about the first month of life, followed by increasingly severe neurological abnormalities, and death by approximately 10 weeks of life. 75,76 The mutant behavioral phenotype includes hypoactivity, body trembling, gait ataxia, and limb clasping. Picker et al 36 utilized a neonatal screen of tests for sensorimotor development and ultrasonic vocalizations in the Rett syndrome-model mice .…”

“…81 An abnormal phenotype is still observed when the loss of Mecp2 is limited to forebrain areas and to postnatal development. 75,80 In particular, the conditional Mecp2-null mice still show forelimb and hindlimb clasping, motor impairment and ataxic gait, and decreased social preference. 75,80 However, some behavioral alterations emerge at a later time point than observed with prenatal loss of Mecp2 function, 75 or, in the case of general hypoactivity or reduced context-dependent fear conditioning, are not observed.…”

“…75,80 In particular, the conditional Mecp2-null mice still show forelimb and hindlimb clasping, motor impairment and ataxic gait, and decreased social preference. 75,80 However, some behavioral alterations emerge at a later time point than observed with prenatal loss of Mecp2 function, 75 or, in the case of general hypoactivity or reduced context-dependent fear conditioning, are not observed. 80 These studies demonstrate that embryonic loss of Mecp2 is not necessary to induce behavioral changes, which is relevant to the normal early development seen in the clinical disorder.…”

Rett Syndrome: Reaching for Clinical Trials

“…The M e C P 2 p r o t e i n b i n d s m e t h y l c y t o s i n e a n d 5 -hydroxymethycytosine at CpG sites in promoter regions of target genes, controlling their transcription by recruiting corepressors and co-activators. Mecp2 knockout mouse models demonstrated that MeCP2 is critical for the maturation and maintenance of neurons and glial cells [14,15]. Thereafter, Mecp2 knockout and knockin mice carrying mutations observed in RTT individuals allowed fundamental research to advance our understanding of the molecular, cellular, and systems-level pathology [16], and to begin addressing possible therapeutic interventions.…”