The transcriptional repressor Mecp2 regulates terminal neuronal differentiation

Matarazzo, Valéry; Cohen, Deborah R.S; Palmer, Amy M.; Simpson, P. Jeanette; Khokhar, Babar; Pan, Shih Jung; Ronnett, Gabriele V.

doi:10.1016/j.mcn.2004.05.005

Cited by 73 publications

(88 citation statements)

References 74 publications

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“…This hypothesis is consistent with previous reports indicating a greater percentage of immature neurons in the olfactory epithelium of Mecp2 KO mice (Matarazzo et al, 2004), and with histone H3 lysine-9 acetylation and methylation patterns seen in Mecp2-deficient RTT human brains that correspond to an arrest at the transitioning stage of neuronal maturation (Kawasaki et al, 2005). Future studies will be needed to define how Mecp2 regulates the expression of genes critical for this transitioning stage.…”

Section: Discussionsupporting

confidence: 92%

Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons

Smrt

Eaves-Egenes

Barkho

et al. 2007

Neurobiology of Disease

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It is well known that Rett Syndrome, a severe postnatal childhood neurological disorder is mostly caused by mutations in the MECP2 gene. However, how deficiencies in MeCP2 contribute to the neurological dysfunction of Rett Syndrome is not clear. We aimed to resolve the role of MeCP2 epigenetic regulation in postnatal brain development in a Mecp2-deficient mouse model. We found that, while Mecp2 was not critical for the production of immature neurons in the dentate gyrus (DG) of the hippocampus, the newly generated neurons exhibited pronounced deficits in neuronal maturation, including delayed transition into a more mature stage, altered expression of presynaptic proteins, and reduced dendritic spine density. Furthermore, analysis of gene expression profiles of isolated DG granule neurons revealed abnormal expression levels of a number of genes previously shown to be important for synaptogenesis. Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis.

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Section: Discussionsupporting

confidence: 92%

Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons

Smrt

Eaves-Egenes

Barkho

et al. 2007

Neurobiology of Disease

208

222

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“…Small GTPases have a crucial role in cytoskeleton dynamics, Truncating IQSEC2 mutations in severe ID F Tran Mau-Them et al suggesting a common physiological pathway via abnormal small GTPase signalling [11][12][13][14][15][16][17] in patients with severe ID, seizures, postnatal microcephaly and stereotypic midlines movements.…”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability

et al. 2013

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Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C. Keywords: syndromic X-linked intellectual disability; microcephaly; IQSEC2-truncating mutations INTRODUCTIONIntellectual disability (ID) is defined by substantial limitations in cognitive functioning (intellectual quotient o70) coupled with a deficit in adaptive behaviour and onset before the age of 18 years. ID is frequent in the general population, with as many as 1 in every 50 individuals directly affected worldwide. 1,2 Among the genetic etiologies of ID, XLID is a frequent cause, estimated at 5-10% of all cases in males, with a major genetic heterogeneity. Indeed, more than 102 genes have been involved in syndromic form of XLID, making molecular diagnosis and thus genetic counselling difficult. 2-4 Among XLID, syndromic and nonsyndromic forms are delineated based on observed additional features that are associated with ID such as seizures, abnormal growth parameters, visceral or cerebral malformation, and so on. Recently, mutations in IQSEC2 (Sec7 domain of, and IQ-like domain) have been shown to cause nonsyndromic XLID with behavioural disturbance. 5-8 We report on three male patients with severe syndromic XLID and truncating mutations in IQSEC2. PATIENTS AND METHODS Patient 1This patient was referred to the Genetics Department for severe ID and postnatal microcephaly. He is the only child born to healthy unrelated parents native to the south of France. Pregnancy was uneventful. The boy was born at 37 ½ weeks of gestation full term by caesarean section due to an abnormal presentation. Birth measurements were in the normal range (occipital frontal circumference (OFC) 36 cm, þ 1 SD; birth weight 3430 g, mean; birth length 52.5 cm, þ 1 SD). Postnatal course was marked by psychomotor retardation with neonatal hypotonia, hyperkinesia, strabismus and non-inherited progressive postnatal microcephaly with OFC at À2 SD at 6 months of age. He sat at 12 months and did not vocalize at 15 months. At the time of the last evaluation, he was 4 years old. He presented with normal facial features ( Figure 1a). OFC was at 48 cm, À2.5 SD; weight at 2 kg, þ 2 SD and length at 106 cm, þ 1 SD. Language was not acquired and he could not walk alone. He h...

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“…Within neurons, MeCP2 plays critical roles in neuronal maturation (Kishi and Macklis 2004;Fukuda et al 2005;Kishi and Macklis 2010), terminal neuronal differentiation (Matarazzo et al 2004;Tsujimura et al 2009), modulating the neuronal morphology (Ballas et al 2009;Belichenko et al 2009b;Wang et al 2013a;Rastegar et al 2009;Belichenko et al 2009a;Larimore et al 2009) and synaptic plasticity (Chao et al 2007;Qiu et al 2012;Na et al 2012Na et al , 2013Zhong et al 2012). Most recent studies demonstrate the role of MeCP2 in regulating protein synthesis, and it is suggested that the reduced protein synthesis in MeCP2-deficient cells is contributing to the RTT phenotypes detected in these cells (Li et al 2013;Ricciardi et al 2011).…”

Section: Other Biological Functions Of Mecp2mentioning

confidence: 99%

Rett Syndrome and MeCP2

2014

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Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

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The transcriptional repressor Mecp2 regulates terminal neuronal differentiation

Cited by 73 publications

References 74 publications

Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons

Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons

Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability

Rett Syndrome and MeCP2

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