Expression of nuclear Methyl-CpG binding protein 2 (Mecp2) is dependent on neuronal stimulation and application of Insulin-like growth factor 1

Tropea, Daniela; Mortimer, Niall; Bellini, Stefania; Molinos, Inés; Sanfeliu, Albert; Shovlin, Stephen; McAllister, Donna; Gill, Michael; Mitchell, Kevin J.; Corvin, Aiden

doi:10.1016/j.neulet.2016.04.024

Cited by 12 publications

(10 citation statements)

References 23 publications

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“…It is also of note that as a miR132 target (Klein et al, 2007), Mecp2 mRNA levels were reduced in the hippocampus of EE-reared mice, suggesting that environmental stimulation diminishes Mecp2 expression. Interestingly, similar observations have been reported for cultured cortical neurons exposed to stimuli inducing neuronal activation (Tropea et al, 2016). Our results extend this in vitro observation to a mouse model subjected to an environmental paradigm that increases neuronal activity.…”

Section: Discussionsupporting

confidence: 85%

Mecp2 Mediates Experience-Dependent Transcriptional Upregulation of Ryanodine Receptor Type-3

Torres

Hidalgo

Kerr

2017

Front. Mol. Neurosci.

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Mecp2 is a DNA methylation reader that plays a critical role in experience-dependent plasticity. Increasing evidence supports a role for epigenetic modifications in activity-induced gene expression. Hence, candidate genes related to such phenomena are of great interest. Ryanodine receptors are intracellular calcium channels that contribute to hippocampal synaptic plasticity, dendritic spine remodeling, and participate in learning and memory processes. Here we exposed mice to the enriched environment (EE) paradigm, which through increased stimulation induces experience dependent-plasticity, to explore a role for methyl-cytosines, and Mecp2 in directing Ryanodine receptor 3 (Ryr3) transcriptional activity. EE induced a hippocampal-specific increase in the methylation of discrete cytosines located at a Ryr3 isoform promoter; chromatin immunoprecipitation experiments revealed that EE increased Mecp2 binding to this Ryr3 isoform promoter. Interestingly, the experimental paradigm induced robust Ryr3 upregulation, accompanied by miR132-dependent suppression of p250GAP, a pathway driving synaptogenesis. In contrast to WT mice, Mecp2-null mice showed diminished levels of Ryr3 and displayed impaired EE-induced Ryr3 upregulation, compromising miR132 dependent suppression of p250GAP and experience-dependent structural plasticity. Based on these results, we propose that Mecp2 acts as a transcriptional activator of Ryr3, contributing to experience-dependent plasticity.

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Section: Discussionsupporting

confidence: 85%

Mecp2 Mediates Experience-Dependent Transcriptional Upregulation of Ryanodine Receptor Type-3

Torres

Hidalgo

Kerr

2017

Front. Mol. Neurosci.

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“…The third potential mechanism relates to effects on transcription. This has been demonstrated in recent studies of IGF-1 on mecp2 transcript (Tropea et al, 2016 ). More work is needed to clarify the direct and indirect effects of IGF1 and derivates, and their action in different cell types.…”

Section: Potential Molecular Mechanisms Of Igf1 and Derivates In Diffsupporting

confidence: 60%

“…One mechanism by which IGF-1 exerts its effects in RTT may be by acting on its canonical signaling pathways (such as PI3K and MAPK pathways as above). Interestingly, a recent study demonstrates that IGF-1 application may actually increase nuclear MeCP2 transcript and protein (Tropea et al, 2016 ). Activity dependent plasticity was also shown to modulate MeCP2 expression and this additionally demonstrates the profound effects of IGF-1 on cellular neuroplasticity in the CNS.…”

Section: Rett Syndromementioning

confidence: 99%

Insulin-Like Growth Factor 1 and Related Compounds in the Treatment of Childhood-Onset Neurodevelopmental Disorders

2016

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Insulin-Like Growth Factor 1 (IGF-1) is a neurotrophic polypeptide with crucial roles to play in Central Nervous System (CNS) growth, development and maturation. Following interrogation of the neurobiology underlying several neurodevelopmental disorders and Autism Spectrum Disorders (ASD), both recombinant IGF-1 (mecasermin) and related derivatives, such as (1-3)IGF-1, have emerged as potential therapeutic approaches. Clinical pilot studies and early reports have supported the safety/preliminary efficacy of IGF-1 and related compounds in the treatment of Rett Syndrome, with evidence mounting for its use in Phelan McDermid Syndrome and Fragile X Syndrome. In ASD, clinical trials are ongoing. Here, we review the role of IGF-1 in the molecular etiologies of these conditions in addition to the accumulating evidence from early clinical studies highlighting the possibility of IGF-1 and related compounds as potential treatments for these childhood-onset neurodevelopmental disorders.

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“…In the RTT condition, however, insufficient IGF-1 level will cause poor activation of this pathway and under phosphorylation of the AKT, which in turn reduces the inhibitory effect on PKC, resulting in over phosphorylation of FXYD1. In addition, Tropea et al (2016) found that IGF-1 could increase MeCP2 mRNA levels and the nuclear localization of MeCP2 protein, increase the copy number of wild-type MeCP2, and improve the symptoms of RTT. Therefore, IGF-1 may increase the wild-type MeCP2 level, at least in some chimeric condition, resulting in the inhibition of the FXYD1 gene transcription.…”

Section: Discussionmentioning

confidence: 98%

Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome

et al. 2020

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Rett syndrome (RTT) is a neurodevelopmental disease in children that is mainly caused by mutations in the MeCP2 gene, which codes for a transcriptional regulator. The expression of insulin-like growth factor-1 (IGF-1) is reduced in RTT patients and animal models, and IGF-1 treatment is a promising therapeutic strategy for RTT. However, the mechanism underlying the effects of IGF-1 remains to be further explored. FXYD1 is an auxiliary subunit of Na, K-ATPase. Overexpression of FXYD1 is involved in the pathogenesis of RTT. However, whether IGF-1 exerts its effect through normalizing FXYD1 is completely unknown. To this end, we evaluated the effect of IGF-1 on FXYD1 expression and posttranslational modification in a mouse model of RTT (MeCP2 308) using both in vitro and in vivo experiments. The results show that FXYD1 mRNA and phosphorylated protein (p-FXYD1) were significantly elevated in the frontal cortex in RTT mice, compared to wild type. In RTT mice, IGF-1 treatment significantly reduced levels of FXYD1 mRNA and p-FXYD1, in parallel with improvements in behavior, motor coordination, and cognitive function. For mechanistic insight into the effect of IGF-1 on p-FXYD1, we found the decreased phosphorylated forms of PI3K-AKT-mTOR signaling pathway components in the frontal cortex of RTT mice and the normalizing effect of IGF-1 on the phosphorylated forms of these components. Interestingly, blocking the PI3K/AKT pathway by PI3K inhibitor could abolish the effect of IGF-1 on p-FXYD1 level, in addition to the effect of IGF-1 on the phosphorylation of other components in the PI3K/AKT pathway. Thus, our study has provided new insights into the mechanism of IGF-1 treatment for RTT, which appears to involve FXYD1.

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Expression of nuclear Methyl-CpG binding protein 2 (Mecp2) is dependent on neuronal stimulation and application of Insulin-like growth factor 1

Cited by 12 publications

References 23 publications

Mecp2 Mediates Experience-Dependent Transcriptional Upregulation of Ryanodine Receptor Type-3

Mecp2 Mediates Experience-Dependent Transcriptional Upregulation of Ryanodine Receptor Type-3

Insulin-Like Growth Factor 1 and Related Compounds in the Treatment of Childhood-Onset Neurodevelopmental Disorders

Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome

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