Synaptic Signaling and Aberrant RNA Splicing in Autism Spectrum Disorders

Smith, Ryan M.; Sadée, Wolfgang

doi:10.3389/fnsyn.2011.00001

Cited by 46 publications

(38 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is consistent with previous results showing that genes associated with transcriptional regulation were downregulated in ASD 48. It has been well established that epigenetic and post‐transcriptional regulation have pivotal roles in the pathogenesis of neurodevelopmental disorders, including ASD 49. In agreement with this finding, genome‐wide transcriptomic analysis identified differential splicing events in post‐mortem ASD brains, which were associated with neuronal activity‐dependent gene regulation 50.…”

Section: Discussionsupporting

confidence: 92%

Maternal immune activation alters brain microRNA expression in mouse offspring

Sunwoo

Jeon²,

Moon

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveMaternal immune activation (MIA) is associated with an increased risk of autism spectrum disorder (ASD) in offspring. Herein, we investigate the altered expression of microRNAs (miRNA), and that of their target genes, in the brains of MIA mouse offspring.MethodsTo generate MIA model mice, pregnant mice were injected with polyriboinosinic:polyribocytidylic acid on embryonic day 12.5. We performed miRNA microarray and mRNA sequencing in order to determine the differential expression of miRNA and mRNA between MIA mice and controls, at 3 weeks of age. We further identified predicted target genes of dysregulated miRNAs, and miRNA‐target interactions, based on the inverse correlation of their expression levels.ResultsMice prenatally subjected to MIA exhibited behavioral abnormalities typical of ASD, such as a lack of preference for social novelty and reduced prepulse inhibition. We found 29 differentially expressed miRNAs (8 upregulated and 21 downregulated) and 758 differentially expressed mRNAs (542 upregulated and 216 downregulated) in MIA offspring compared to controls. Based on expression levels of the predicted target genes, 18 downregulated miRNAs (340 target genes) and three upregulated miRNAs (60 target genes) were found to be significantly enriched among the differentially expressed genes. miRNA and target gene interactions were most significant between mmu‐miR‐466i‐3p and Hfm1 (ATP‐dependent DNA helicase homolog), and between mmu‐miR‐877‐3p and Aqp6 (aquaporin 6).InterpretationOur results provide novel information regarding miRNA expression changes and their putative targets in the early postnatal period of brain development. Further studies will be needed to evaluate potential pathogenic roles of the dysregulated miRNAs.

show abstract

Section: Discussionsupporting

confidence: 92%

Maternal immune activation alters brain microRNA expression in mouse offspring

Sunwoo

Jeon²,

Moon

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…2, namely 1) MECP2 influences global translation by enhancing the AKT/mTOR signaling pathway [46], 2) Alternative splicing of downstream gene products is affected because MECP2 forms a complex with YB1, an important splicing factor [29, 47–51], 3) Expression of various microRNAs and long non-coding RNAs is regulated by MECP2 (20, 45, 47–49), and 4) MECP2 triggers the chromatin compaction at methylated DNA sites which regulates the transcription of adjacent genes (34, 37–41). The last one is an important (and best investigated) pathway and will be explained in detail below.…”

Section: Mecp2 Functionmentioning

confidence: 99%

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Ehrhart

Coort

Cirillo

et al. 2016

Orphanet J Rare Dis

View full text Add to dashboard Cite

Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. Typical symptoms are onset at month 6–18 after normal pre- and postnatal development, loss of acquired skills and severe intellectual disability. The type and severity of symptoms are individually highly different. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels although the molecular pathways from gene to phenotype are currently not fully understood. In this review the known changes in metabolite levels, gene expression and biological pathways in RTT are summarized, discussed how they are leading to some characteristic RTT phenotypes and therefore the gaps of knowledge are identified. Namely, which phenotypes have currently no mechanistic explanation leading back to MECP2 related pathways? As a result of this review the visualization of the biologic pathways showing MECP2 up- and downstream regulation was developed and published on WikiPathways which will serve as template for future omics data driven research. This pathway driven approach may serve as a use case for other rare diseases, too.

show abstract

“…Recently, it has also been shown that the DNA methylation-dependent binding of MeCP2 to exonic sequences modulates alternative splicing (Maunakea et al 2013). Altered RNA splicing of synaptic genes have been reported in autism as well as Rett syndrome (Smith and Sadee 2011). However, whether MeCP2 plays a role in RNA splicing in autism is currently unknown.…”

Section: Mecp2 In Rna Splicingmentioning

confidence: 99%

Rett Syndrome and MeCP2

2014

View full text Add to dashboard Cite

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.

show abstract

Synaptic Signaling and Aberrant RNA Splicing in Autism Spectrum Disorders

Cited by 46 publications

References 97 publications

Maternal immune activation alters brain microRNA expression in mouse offspring

Maternal immune activation alters brain microRNA expression in mouse offspring

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Rett Syndrome and MeCP2

Contact Info

Product

Resources

About