Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder–like Behavior

International audienceBACKGROUND: Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into "when" and "where" TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. METHODS: We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3 flox/flox with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. RESULTS: These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, w50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic syn-apse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. CONCLUSIONS: Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency

Yeast Mitochondrial Biogenesis: A Role for the PUF RNA-Binding Protein Puf3p in mRNA Localization

The asymmetric localization of mRNA plays an important role in coordinating posttranscriptional events in eukaryotic cells. We investigated the peripheral mitochondrial localization of nuclear-encoded mRNAs (MLR) in various conditions in which the mRNA binding protein context and the translation efficiency were altered. We identified Puf3p, a Pumilio family RNA-binding protein, as the first trans-acting factor controlling the MLR phenomenon. This allowed the characterization of two classes of genes whose mRNAs are translated to the vicinity of mitochondria. Class I mRNAs (256 genes) have a Puf3p binding motif in their 3'UTR region and many of them have their MLR properties deeply affected by PUF3 deletion. Conversely, mutations in the Puf3p binding motif alter the mitochondrial localization of BCS1 mRNA. Class II mRNAs (224 genes) have no Puf3p binding site and their asymmetric localization is not affected by the absence of PUF3. In agreement with a co-translational import process, we observed that the presence of puromycin loosens the interactions between most of the MLR-mRNAs and mitochondria. Unexpectedly, cycloheximide, supposed to solidify translational complexes, turned out to destabilize a class of mRNA-mitochondria interactions. Classes I and II mRNAs, which are therefore transported to the mitochondria through different pathways, correlated with different functional modules. Indeed, Class I genes code principally for the assembly factors of respiratory chain complexes and the mitochondrial translation machinery (ribosomes and translation regulators). Class II genes encode proteins of the respiratory chain or proteins involved in metabolic pathways. Thus, MLR, which is intimately linked to translation control, and the activity of mRNA-binding proteins like Puf3p, may provide the conditions for a fine spatiotemporal control of mitochondrial protein import and mitochondrial protein complex assembly. This work therefore provides new openings for the global study of mitochondria biogenesis

Transcriptome Analysis Describing New Immunity and Defense Genes in Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis Patients

Background: Large-scale gene expression profiling of peripheral blood mononuclear cells from Rheumatoid Arthritis (RA) patients could provide a molecular description that reflects the contribution of diverse cellular responses associated with this disease. The aim of our study was to identify peripheral blood gene expression profiles for RA patients, using Illumina technology, to gain insights into RA molecular mechanisms. Methodology/Principal Findings: The Illumina Human-6v2 Expression BeadChips were used for a complete genome-wide transcript profiling of peripheral blood mononuclear cells (PBMCs) from 18 RA patients and 15 controls. Differential analysis per gene was performed with one-way analysis of variance (ANOVA) and P values were adjusted to control the False Discovery Rate (FDR < 5%). Genes differentially expressed at significant level between patients and controls were analyzed using Gene Ontology (GO) in the PANTHER database to identify biological processes. A differentially expression of 339 Reference Sequence genes (238 down-regulated and 101 up-regulated) between the two groups was observed. We identified a remarkably elevated expression of a spectrum of genes involved in Immunity and Defense in PBMCs of RA patients compared to controls. This result is confirmed by GO analysis, suggesting that these genes could be activated systemically in RA. No significant down-regulated ontology groups were found. Microarray data were validated by real time PCR in a set of nine genes showing a high degree of correlation. Conclusions/Significance: Our study highlighted several new genes that could contribute in the identification of innovative clinical biomarkers for diagnostic procedures and therapeutic interventions

Epidemiology and outcome predictors in 450 patients with hanging-induced cardiac arrest: a retrospective study

BackgroundCardiac arrest is the most life-threatening complication of attempted suicide by hanging. However, data are scarce on its characteristics and outcome predictors.MethodsThis retrospective observational multicentre study in 31 hospitals included consecutive adults admitted after cardiac arrest induced by suicidal hanging. Factors associated with in-hospital mortality were identified by multivariate logistic regression with multiple imputations for missing data and adjusted to the temporal trends over the study period.ResultsOf 450 patients (350 men, median age, 43 [34–52] years), 305 (68%) had a psychiatric history, and 31 (6.9%) attempted hanging while hospitalized. The median time from unhanging to cardiopulmonary resuscitation was 0 [0–5] min, and the median time to return of spontaneous circulation (ROSC) was 20 [10–30] min. Seventy-nine (18%) patients survived to hospital discharge. Three variables were independently associated with higher in-hospital mortality: time from collapse or unhanging to ROSC&gt;20 min (odds ratio [OR], 4.71; 95% confidence intervals [95%CIs], 2.02–10.96; p = 0.0004); glycaemia &gt;1.4 g/L at admission (OR, 6.38; 95%CI, 2.60–15.66; p &lt; 0.0001); and lactate &gt;3.5 mmol/L at admission (OR, 6.08; 95%CI, 1.71–21.06; p = 0.005). A Glasgow Coma Scale (GCS) score of &gt;5 at admission was associated with lower in-hospital mortality (OR, 0.009; 95%CI, 0.02–0.37; p = 0.0009).ConclusionIn patients with hanging-induced cardiac arrest, time from collapse or unhanging to return of spontaneous circulation, glycaemia, arterial lactate, and coma depth at admission were independently associated with survival to hospital discharge. Knowledge of these risk factors may help guide treatment decisions in these patients at high risk of hospital mortality

Searching for susceptibility genes for rhumatoid arthritis and coronary artery disease

La polyarthrite rhumatoïde (PR) et la maladie coronaire (MC) sont deux maladies touchant l'adulte comportant une susceptibilité génétique et partageant plusieurs chapitres physiopathologiques. Nous avons recherché des gènes de susceptibilité à la PR en employant une approche gène-candidat dans des loci suggerés par les données d'études de criblage du genome. Nous avons mis au point une étude originale (Genescaf) d'approche des gènes impliqués dans la MC.Rhumatoid arthritis (RA) and coronary artery disease (CAD) are two adult diseases involving some genetic susceptibility genes and sharing many physiopathogenic chapters. We tried to find some RA susceptibility genes by a candidate-gene approach located in linked loci. We performed an original study (Genescaf) to approach some CAD susceptibility genes

Searching for susceptibility genes for rhumatoid arthritis and coronary artery disease

La polyarthrite rhumatoïde (PR) et la maladie coronaire (MC) sont deux maladies touchant l'adulte comportant une susceptibilité génétique et partageant plusieurs chapitres physiopathologiques. Nous avons recherché des gènes de susceptibilité à la PR en employant une approche gène-candidat dans des loci suggerés par les données d'études de criblage du genome. Nous avons mis au point une étude originale (Genescaf) d'approche des gènes impliqués dans la MC.Rhumatoid arthritis (RA) and coronary artery disease (CAD) are two adult diseases involving some genetic susceptibility genes and sharing many physiopathogenic chapters. We tried to find some RA susceptibility genes by a candidate-gene approach located in linked loci. We performed an original study (Genescaf) to approach some CAD susceptibility genes

Searching for susceptibility genes for rhumatoid arthritis and coronary artery disease

La polyarthrite rhumatoïde (PR) et la maladie coronaire (MC) sont deux maladies touchant l'adulte comportant une susceptibilité génétique et partageant plusieurs chapitres physiopathologiques. Nous avons recherché des gènes de susceptibilité à la PR en employant une approche gène-candidat dans des loci suggerés par les données d'études de criblage du genome. Nous avons mis au point une étude originale (Genescaf) d'approche des gènes impliqués dans la MC.Rhumatoid arthritis (RA) and coronary artery disease (CAD) are two adult diseases involving some genetic susceptibility genes and sharing many physiopathogenic chapters. We tried to find some RA susceptibility genes by a candidate-gene approach located in linked loci. We performed an original study (Genescaf) to approach some CAD susceptibility genes.EVRY-Bib. électronique (912289901) / SudocSudocFranceF

Suivi bilatéral des structures vasculaires dans les images d'angiographie et reconstruction 3-D des branches principales du réseau vasculaire coronarien à partir de deux projections angiographiques

International audienc

CORSEN, a new software dedicated to microscope-based 3D distance measurements: mRNA–mitochondria distance, from single-cell to population analyses

Recent improvements in microscopy technology allow detection of single molecules of RNA, but tools for large-scale automatic analyses of particle distributions are lacking. An increasing number of imaging studies emphasize the importance of mRNA localization in the definition of cell territory or the biogenesis of cell compartments. CORSEN is a new tool dedicated to three-dimensional (3D) distance measurements from imaging experiments especially developed to access the minimal distance between RNA molecules and cellular compartment markers. CORSEN includes a 3D segmentation algorithm allowing the extraction and the characterization of the cellular objects to be processed—surface determination, aggregate decomposition—for minimal distance calculations. CORSEN's main contribution lies in exploratory statistical analysis, cell population characterization, and high-throughput assays that are made possible by the implementation of a batch process analysis. We highlighted CORSEN's utility for the study of relative positions of mRNA molecules and mitochondria: CORSEN clearly discriminates mRNA localized to the vicinity of mitochondria from those that are translated on free cytoplasmic polysomes. Moreover, it quantifies the cell-to-cell variations of mRNA localization and emphasizes the necessity for statistical approaches. This method can be extended to assess the evolution of the distance between specific mRNAs and other cellular structures in different cellular contexts. CORSEN was designed for the biologist community with the concern to provide an easy-to-use and highly flexible tool that can be applied for diverse distance quantification issues