Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE188903 | GEO | 2022/01/03
REPOSITORIES: GEO
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Project description:This project studies TDP43, which is an RNA binding protein implicated in Motor Neuron Disease. As an RNA-binding protein, TDP43 is known to influences poly-adenylation site choice. For this project, we have inserted a single copy of the GFP-tagged TDP43 gene into the FLPIn Locus of HEk293 cells. We use these Hek293 FLipIn lines to instigate the effect of different deletion and mutation constructs of TDP-43 in their ability to rescue the depletion (siRNA) of the endogenous TDP-43 protein. We are comparing siRNA mediated KD in triplicates for each of the 7 cell lines to the Dox-induced rescues in triplicates. We are using a customised Lexogen Quantseq 3’ end sequencing method that allows us to multiplex cDNAs straight after the reverse transcription. The samples were pooled into barcoded sub-groups, each group will have the Lexogen barcode (i7 indices) in addition.
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Project description:RNA_BINDING, identify global RNA binding sites for TDP43 protein
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Project description:Exploring the intricate link between sleep and brain degeneration holds great promise for the development of effective therapeutics. Here we provide novel insights into the role of TDP-43 and Atx2 in regulating sleep and neurodegeneration using Drosophila. We demonstrate that expression of TDP-43 severely disrupts sleep, resulting in reduced sleep duration of the affected animals. Sleep disruption by TDP-43 is completely rescued by Atx2 knockdown. To unravel the underlying mechanism of TDP43 sleep disruption and Atx2-mediated rescue, we conducted brain RNA sequencing analysis from flies expressing TDP-43 with or without Atx2 knockdown. Among RNAseq changes, we observed upregulation of genes associated with small molecule metabolism with TDP-43 expression, followed by their subsequent downregulation upon Atx2 knockdown. Utilizing these Atx2-regulated genes, we conducted an RNAi screen to identify additional sleep modifiers that interact with TDP-43.
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Project description:Genome-wide analysis of rna-TDP43 interactions at single nucleotide resolution in mouse and human embryonic stem cells
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Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer. small RNA seq in SH-SY-5Y, SNB-19 and HT22 (TDP-43 siRNA VS Control siRNA)
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Project description:A pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia is the aggregation of TDP-43. While extensive exploration into the function of TDP-43 has focused entirely in the central nervous system (CNS), the implications in physiology and pathology of the peripheral nervous system (PNS) have long been overlooked. Herein, we demonstrate that deletion of TDP-43 in Schwann cells results in a 50% reduction in peripheral nerve conduction velocity, without any obvious alterations to peripheral compact myelin. Compromised insulatory function of myelin was due to the complete loss of paranodal axoglial junctions flanking the nodes of Ranvier. By contrast, the paranodal junctions in the CNS oligodendrocytes are unaltered upon deletion of TDP-43. Mechanistically, TDP-43 binds directly to Nfasc mRNA, which encodes neurofascin, a key cell adhesion molecule essential for establishing paranodal junctions. TDP-43 binding sites overlap with a cryptic exon of Nfasc such that loss of TDP-43 leads to the retention of this cryptic exon with a premature stop codon, a prerequisite for nonsense-mediated decay. Thus, TDP-43 is required for the proper assembly of nodes of Ranvier that is essential for saltatory conduction by suppressing the cryptic exon in the Nfasc mRNA of the Schwann cells. Our findings indicate a direct involvement of TDP-43 in normal PNS function and suggest that PNS-autonomous dysfunction in saltatory conduction may contribute to TDP-43 proteinopathies.
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Project description:Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43
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Project description:The aim of this study is to understand the mechanisms of TDP-43 neurotoxicity. Here, we perform a RNA-Seq analysis in TDP-43 gain-of-fucntion (GOF) , TDP-43 loss-of-function and wild-type late pupae heads (73-90 hours APF) and perform TDP-43 GOF vs wild type and TDP-43 LOF vs wild-type differential expression analysis to show that both mechanisms presents defects in ecdysone receptor (ECR)-dependeint transcriptional program switching, and strongly deregulate expression from the neuronal microtubule associated protien Map205. RNA-seq was performed in two wild-type D.melanogaster biological replicates (Canton S, w1118 ), four biological replicates for TDP-43 (LOF) with two distinct genotypes (dTDP-43Δ142/Df(2R)106,dTDP-43Δ23/Δ142 ) and two TDP-43 GOF biological replicates (act5c>dTDP-43 ).
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