Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks

Abstract

BackgroundThe Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16 (MMU16), which is partially homologous to human chromosome 21. These mice develop various neuropathological features identified in DS individuals. We analysed the effect of partial triplication of the MMU16 segment on global gene expression in the cerebral cortex, cerebellum and hippocampus of Ts1Cje mice at 4 time-points: postnatal day (P)1, P15, P30 and P84.ResultsGene expression profiling identified a total of 317 differentially expressed genes (DEGs), selected from various spatiotemporal comparisons, between Ts1Cje and disomic mice. A total of 201 DEGs were identified from the cerebellum, 129 from the hippocampus and 40 from the cerebral cortex. Of these, only 18 DEGs were identified as common to all three brain regions and 15 were located in the triplicated segment. We validated 8 selected DEGs from the cerebral cortex (Brwd1, Donson, Erdr1, Ifnar1, Itgb8, Itsn1, Mrps6 and Tmem50b), 18 DEGs from the cerebellum (Atp5o, Brwd1, Donson, Dopey2, Erdr1, Hmgn1, Ifnar1, Ifnar2, Ifngr2, Itgb8, Itsn1, Mrps6, Paxbp1, Son, Stat1, Tbata, Tmem50b and Wrb) and 11 DEGs from the hippocampus (Atp5o, Brwd1, Cbr1, Donson, Erdr1, Itgb8, Itsn1, Morc3, Son, Tmem50b and Wrb). Functional clustering analysis of the 317 DEGs identified interferon-related signal transduction as the most significantly dysregulated pathway in Ts1Cje postnatal brain development. RT-qPCR and western blotting analysis showed both Ifnar1 and Stat1 were over-expressed in P84 Ts1Cje cerebral cortex and cerebellum as compared to wild type littermates.ConclusionsThese findings suggest over-expression of interferon receptor may lead to over-stimulation of Jak-Stat signaling pathway which may contribute to the neuropathology in Ts1Cje or DS brain. The role of interferon mediated activation or inhibition of signal transduction including Jak-Stat signaling pathway has been well characterized in various biological processes and disease models including DS but information pertaining to the role of this pathway in the development and function of the Ts1Cje or DS brain remains scarce and warrants further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-624) contains supplementary material, which is available to authorized users.

Multivalent Chromatin Engagement and Inter-domain Crosstalk Regulate MORC3 ATPase

“…Recent reports have demonstrated that MORC3 is misregulated in the brain of a Down syndrome mouse model (Ling et al, 2014) and anti-MORC3 antibodies are found in most patients with cancer-associated dermatomyositis (Fiorentino et al, 2013), yet the precise role of MORC3 in normal cellular processes and in disease has not been determined. Here, we present detailed genetic, biochemical, and structural analyses of MORC3.…”

The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome

“…While some published gene expression data from early postnatal and adult brain tissue from the Ts1Cje and Ts65Dn mouse models of DS found several pathway changes similar to what has been observed in humans [Saran et al, 2003; Amano et al, 2004; Kahlem et al, 2004; Laffaire et al, 2009; Ling et al, 2014], fetal and neonatal phenotypic changes in DS mouse models have not been extensively studied. It is also unknown how fetal and neonatal molecular changes affect developmental milestones and early postnatal behavior in mouse models of DS.…”

Análise qualitativa e quantitativa da deglutição orofaríngea na Síndrome de Down

“…Pulmonary complications were observed in five cases, as described in the casuistics profile, and the results indicated presence of laryngotracheal aspiration in only one of the cases. These findings suggest that the pulmonary complications present in this population are not only the result of presence of laryngotracheal aspiration, and that issues such as GER and cardiac conditions deserve emphasis in the investigation of pulmonary complications (13) . Aspiration of reflux content is common in the pediatric population diagnosed with GER (14) , generating complaints about gagging during feeding, which may be mistaken for oropharyngeal symptoms.…”

“…The specialized literature suggests that this modulation occurs with the activation of various cortical and subcortical areas of the central nervous system. Thus, it is worth emphasizing that not only the presence of alterations in the myofunctional orofacial aspects of DS, but also other changes in morphophysiological bases of the central nervous system (CNS) could contribute to impair oral phase modulation (12,13) .…”