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Rôle du microARN 146a dans le développement cérébral et pertinence pour les maladies du neurodéveloppement

Abstract : Developmental brain disorders (DBD) encompass a group of diseases characterised by impairments in cognition, communication, behaviour or motor functioning as a result of atypical brain development. This group includes intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder, specific learning disorder and motor disorders. With an overall prevalence of 3 %, DBD accounts for 10% of the total health care cost in Western countries and is thus a major medical and socio-economical challenge. MicroRNAs (miRNAs) are small non coding RNAs of ~20-22 nucleotides. They play a key role in post-transcriptional gene expression regulation by targeting specific messenger RNA (mRNA) for degradation or translation repression. miRNAs are key mediator of gene expression as each of them can target hundreds of transcripts. miRNAs are expressed throughout the development and life of most eukaryote organisms and regulate a wide range of biological processes including brain development. Consistently, several miRNAs have been associated with neurological pathologies such as Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS) but also with (DBD) namely ASD, ID and epilepsy. Expression studies performed on various sources of samples from ASD patients identified miR-146a as the most commonly deregulated miRNA. It has been reported in four different cohorts and tissue types including post-mortem brain, olfactory mucosal stem cells, fibroblasts and lymphoblastoid cell lines. Abnormal miR-146a expression has also been reported in ID and epilepsy. Importantly, modulating the expression of this particular miRNA was shown to reduce the latency, the duration as well as the intensity of the induced epilepsy in rodent models of telecephalon epilepsy. miR-146a is a known regulator of NFkB, Notch and Wnt/B-catenin pathways and has been associated with cancers and inflammatory disorders but little is known about its functions in the brain. A body of in vitro work describes the role of miR-146a in neuron survival and apoptosis, axonal growth and AMPA receptor endocytosis. Our group also showed the pro-neuronal effects of miRNA overexpression in a H9 model of human neural stem cells. Altogether, these data provide insight into the roles of miR-146a in cultured cells but give no indication on its functions in vivo during neurodevelopment. To investigate this aspect further, we studied a miR146a-/- mouse model using a combination of imaging, molecular and cell biology techniques as well as behavioral studies. We first demonstrated that neurogenesis is altered in miR146a-/-mice. At embryonic day 14 (E14), mutant embryos display increased number of neural progenitors committed towards a neuronal fate as well as more post-mitotic neurons in the neocortex compared to controls. Using primary cell cultures,we found that loss of miR-146a causes increased neurite outgrowth and impaired astrocyte glutamate uptake capacities and we proved the glutamate transporter GLT-1 to be a direct target of miR-146a. Transcriptomic analyses of brain samples at E14, P30 and P60 indicated spatial- and temporal-specific effects of miR-146a inactivation and, consistent with our findings, we observed that loss of miR-146a mainly impacts neuron development. Lastly, brain MRI and behavior investigations revealed an abnormal hippocampal anatomy as well as impaired learning capacities in mutant mice. This work reports the first characterization of a mouse model inactivated for a miRNA in the context of neurodevelopment. We demonstrated the role of miR-146a in brain development and its role in the control of the balance between neural progenitor cell renewal and neuronal differentiation. Lastly, we show the relevance of the miR146a-/-mouse model to study DBD as several aspects recapitulate the features observed in patients, including impaired neurogenesis, abnormal brain anatomy and learning deficits.
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Julien Fregeac. Rôle du microARN 146a dans le développement cérébral et pertinence pour les maladies du neurodéveloppement. Génétique humaine. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB120⟩. ⟨tel-02517307⟩

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