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International audience; Autism spectrum disorders (ASD) are heritable neurodevelopmental conditions characterized by impairment in social interaction and communication and restricted, repetitive, stereotyped patterns of behavior. ASD likely involve deregulation of multiple genes related to brain function and development. MicroRNAs (miRNAs) are post-transcriptional regulators that play key roles in brain development, synapse formation and fine-tuning of genes underlying synaptic plasticity and memory formation. Here, we review recent studies providing genetic and molecular links between miRNA deregulation and ASD pathophysiology. These findings highlight the potential of miRNAs as both biomarkers and therapeutic tools in ASD.

Background MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs have emerged as important modulators of brain development and neuronal function and are implicated in several neurological diseases. Previous studies found miR-146a upregulation is the most common miRNA deregulation event in neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID). Yet, how miR-146a upregulation affects the developing fetal brain remains unclear. Methods We analyzed the expression of miR-146a in the temporal lobe of ASD children using Taqman assay. To assess the role of miR-146a in early brain development, we generated and characterized stably induced H9 human neural stem cell (H9 hNSC) overexpressing miR-146a using various cell and molecular biology techniques. Results We first showed that miR-146a upregulation occurs early during childhood in the ASD brain. In H9 hNSC, miR-146a overexpression enhances neurite outgrowth and branching and favors differentiation into neuronal like cells. Expression analyses revealed that 10% of the transcriptome was deregulated and organized into two modules critical for cell cycle control and neuronal differentiation. Twenty known or predicted targets of miR-146a were significantly deregulated in the modules, acting as potential drivers. The two modules also display distinct transcription profiles during human brain development, affecting regions relevant for ASD including the neocortex, amygdala, and hippocampus. Cell type analyses indicate markers for pyramidal, and interneurons are highly enriched in the deregulated gene list. Up to 40% of known markers of newly defined neuronal lineages were deregulated, suggesting that miR-146a could participate also in the acquisition of neuronal identities. Conclusion Our results demonstrate the dynamic roles of miR-146a in early neuronal development and provide new insight into the molecular events that link miR-146a overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies. Electronic supplementary material The online version of this article (10.1186/s13229-018-0219-3) contains supplementary material, which is available to authorized users.

To the editor: In juvenile myelomonocytic leukemia (JMML), activating RAS mutations are responsible for a hyperactive RAS/ERK signaling.[1][1] Somatic codons 12-13-61 RAS mutations are described in cases of RAS -associated lymphoproliferative disease (RALD),[2][2][⇓][3]-[4][4] believed to be a

Background Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. Methods miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. Results We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients’ cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. Conclusions While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. Electronic supplementary material The online version of this article (doi:10.1186/s13229-015-0064-6) contains supplementary material, which is available to authorized users.

Les troubles du spectre autistique sont un groupe de troubles neurodeveloppementaux causes par l’interaction entre des facteurs genetiques, epigenetiques et environnementaux. Parmi les facteurs epigenetiques, les microARNs (miARN) jouent un role cle dans le developpement neural et la formation des synapses. Nous et d’autres equipes avons recemment identifie la sur-expression du miARN miR-146a comme un marqueur commun a differents types de cellules issus des patients autistes : des cellules souches des muqueuses olfactives, des fibroblastes primaires et des lignees cellulaires lymphoblastoides. Ici, nous montrons par RT-qPCR que miR-146a est egalement sur-exprime dans le lobe temporal des enfants autistes (4–10 ans) mais pas chez les adolescents ni les adultes. Pour comprendre son role dans le developpement precoce, nous avons genere des lignees de cellules souches neurales humaines H9 sur-exprimant de facon stable miR-146a. Nous demontrons qu’a l’etat indifferencie la sur-expression du miR-146a n’a aucun effet sur la proliferation et le taux d’apoptose de ces cellules. En revanche, dans des conditions de differentiation, miR-146a accelere significativement la croissance et le branchement des neurites et favorise la differenciation en neurones. Par ailleurs, des analyses transcriptomiques par ARN-Seq realisees a partir des cellules differenciees demontrent que 10 % des transcrits detectes sont significativement deregules (p 1,5). En particulier, la majorite des marqueurs specifiques des different types neuronaux et des differentes couches du cortex (26/44) sont affectees, suggerant que miR-146a joue un role dans la differenciation et l’acquisition de l’identite des cellules neurales. Ces resultats sont coherents avec la desorganisation de l’architecture corticale et l’anomalie de formation des six differentes couches du cortex observes chez des patients autistes. Ils confirment le role de la sur-expression de miR-146a dans l’etiologie de la maladie.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and a major cause of stroke. In the mammalian heart the gap junction proteins connexin40 (Cx40) and connexin43 (Cx43) are strongly expressed in the atrial myocardium mediating effective propagation of electrical impulses. Different heterozygous mutations in the coding region for Cx40 were identified in patients with AF. We have generated transgenic Cx40A96S mice harboring one of these mutations, the loss-of-function Cx40A96S mutation, as a model for atrial fibrillation. Cx40A96S mice were characterized by immunochemical and electrophysiological analyses. Significantly reduced atrial conduction velocities and strongly prolonged episodes of atrial fibrillation were found after induction in Cx40A96S mice. Analyses of the gating properties of Cx40A96S channels in cultured HeLa cells also revealed significantly lower junctional conductance and enhanced sensitivity voltage gating of Cx40A96S in comparison to Cx40 wild-type gap junctions. This is caused by reduced open probabilities of Cx40A96S gap junction channels, while single channel conductance remained the same. Similar to the corresponding patient, heterozygous Cx40A96S mice revealed normal expression levels and localization of the Cx40 protein. We conclude that heterozygous Cx40A96S mice exhibit prolonged episodes of induced atrial fibrillation and severely reduced atrial conduction velocities similar to the corresponding human patient.

Neuronal gap junction (GJ) channels composed of connexin36 (Cx36) play an important role in neuronal synchronization and network dynamics. Here we show that Cx36-containing electrical synapses between inhibitory neurons of the thalamic reticular nucleus are bidirectionally modulated by changes in intracellular free magnesium concentration ([Mg(2+)]i). Chimeragenesis demonstrates that the first extracellular loop of Cx36 contains a Mg(2+)-sensitive domain, and site-directed mutagenesis shows that the pore-lining residue D47 is critical in determining high Mg(2+)-sensitivity. Single-channel analysis of Mg(2+)-sensitive chimeras and mutants reveals that [Mg(2+)]i controls the strength of electrical coupling mostly via gating mechanisms. In addition, asymmetric transjunctional [Mg(2+)]i induces strong instantaneous rectification, providing a novel mechanism for electrical rectification in homotypic Cx36 GJs. We suggest that Mg(2+)-dependent synaptic plasticity of Cx36-containing electrical synapses could underlie neuronal circuit reconfiguration via changes in brain energy metabolism that affects neuronal levels of intracellular ATP and [Mg(2+)]i.