Dataset Information

Early Transcriptional Changes Induced by Wnt/?-Catenin Signaling in Hippocampal Neurons.

ABSTRACT: Wnt/?-catenin signaling modulates brain development and function and its deregulation underlies pathological changes occurring in neurodegenerative and neurodevelopmental disorders. Since one of the main effects of Wnt/?-catenin signaling is the modulation of target genes, in the present work we examined global transcriptional changes induced by short-term Wnt3a treatment (4?h) in primary cultures of rat hippocampal neurons. RNAseq experiments allowed the identification of 170 differentially expressed genes, including known Wnt/?-catenin target genes such as Notum, Axin2, and Lef1, as well as novel potential candidates Fam84a, Stk32a, and Itga9. Main biological processes enriched with differentially expressed genes included neural precursor (GO:0061364, p-adjusted = 2.5 × 10-7), forebrain development (GO:0030900, p-adjusted = 7.3 × 10-7), and stem cell differentiation (GO:0048863 p-adjusted = 7.3 × 10-7). Likewise, following activation of the signaling cascade, the expression of a significant number of genes with transcription factor activity (GO:0043565, p-adjusted = 4.1 × 10-6) was induced. We also studied molecular networks enriched upon Wnt3a activation and detected three highly significant expression modules involved in glycerolipid metabolic process (GO:0046486, p-adjusted = 4.5 × 10-19), learning or memory (GO:0007611, p-adjusted = 4.0 × 10-5), and neurotransmitter secretion (GO:0007269, p-adjusted = 5.3 × 10-12). Our results indicate that Wnt/?-catenin mediated transcription controls multiple biological processes related to neuronal structure and activity that are affected in synaptic dysfunction disorders.

SUBMITTER: Perez-Palma E

PROVIDER: S-EPMC5223035 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Early Transcriptional Changes Induced by Wnt/β-Catenin Signaling in Hippocampal Neurons.

Pérez-Palma Eduardo E Andrade Víctor V Caracci Mario O MO Bustos Bernabé I BI Villaman Camilo C Medina Matías A MA Ávila Miguel E ME Ugarte Giorgia D GD De Ferrari Giancarlo V GV

Neural plasticity 20161227

Wnt/β-catenin signaling modulates brain development and function and its deregulation underlies pathological changes occurring in neurodegenerative and neurodevelopmental disorders. Since one of the main effects of Wnt/β-catenin signaling is the modulation of target genes, in the present work we examined global transcriptional changes induced by short-term Wnt3a treatment (4 h) in primary cultures of rat hippocampal neurons. RNAseq experiments allowed the identification of 170 diff ...[more]

PMID: 28116168

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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder mainly known for synaptic impairment and neuronal cell loss, affecting memory processes. Beside these damages, mitochondria have been implicated in the pathogenesis of AD through the induction of the mitochondrial permeability transition pore (mPTP). The mPTP is a non-selective pore that is formed under apoptotic conditions, disturbing mitochondrial structure and thus, neuronal viability. In AD, Aβ oligomers (Aβos) favor the opening of the pore, activating mitochondria-dependent neuronal cell death cascades. The Wnt signaling activated through the ligand Wnt3a has been described as a neuroprotective signaling pathway against amyloid-β (Aβ) peptide toxicity in AD. However, the mechanisms by which Wnt signaling prevents Aβos-induced neuronal cell death are unclear. We proposed here to study whether Wnt signaling protects neurons earlier than the late damages in the progression of the disease, through the preservation of the mitochondrial structure by the mPTP inhibition. To study specific events related to mitochondrial permeabilization we performed live-cell imaging from primary rat hippocampal neurons, and electron microscopy to analyze the mitochondrial morphology and structure. We report here that Wnt3a prevents an Aβos-induced cascade of mitochondrial events that leads to neuronal cell death. This cascade involves (a) mPTP opening, (b) mitochondrial swelling, (c) mitochondrial membrane potential loss and (d) cytochrome c release, thus leading to neuronal cell death. Furthermore, our results suggest that the activation of the Wnt signaling prevents mPTP opening by two possible mechanisms, which involve the inhibition of mitochondrial GSK-3β and/or the modulation of mitochondrial hexokinase II levels and activity. This study suggests a possible new approach for the treatment of AD from a mitochondrial perspective, and will also open new lines of study in the field of Wnt signaling in neuroprotection.

Dataset Information

Early Transcriptional Changes Induced by Wnt/?-Catenin Signaling in Hippocampal Neurons.

Publications

Early Transcriptional Changes Induced by Wnt/<i>β</i>-Catenin Signaling in Hippocampal Neurons.

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