Dataset Information

Integrated transcriptomic and metabolomic analysis of cortical neurons reveals dysregulated lipid metabolism, enhanced glycolysis and activated HIF-1 signaling pathways in acute hypoxia.

ABSTRACT: The brain is the main oxygen-consuming organ and is vulnerable to ischemic shock or insufficient blood perfusion. Brain hypoxia has a persistent and detrimental effect on resident neurons. Previous studies have identified alterations in genes and metabolites in ischemic brain shock by single omics, but the adaptive systems that neurons use to cope with hypoxia remain uncovered. In the present study, we constructed an acute hypoxia model and performed a multi-omics analysis from RNA-sequencing and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics on exploring potentially differentially expressed genes (DEGs) and metabolites (DEMs) in primary cortical neurons under severe acute hypoxic conditions. The TUNEL assay showed acute hypoxia-induced apoptosis in cortical neurons. Omics analysis identified 564 DEGs and 46 DEMs categorized in the Kyoto encyclopedia of genes and genomes (KEGG) database. Integrative pathway analysis highlighted that dysregulated lipid metabolism, enhanced glycolysis, and activated HIF-1 signaling pathways could regulate neuron physiology and pathophysiology under hypoxia. These findings may help us understand the transcriptional and metabolic mechanisms by which cortical neurons respond to hypoxia and identify potential targets for neuron protection.

SUBMITTER: Zhang W

PROVIDER: S-EPMC10070144 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Integrated transcriptomic and metabolomic analysis of cortical neurons reveals dysregulated lipid metabolism, enhanced glycolysis and activated HIF-1 signaling pathways in acute hypoxia.

Zhang Wenyi W Han Bo B Zhang Huijun H Fu Rao R Lu Yinzhong Y Zhang Guangming G

Heliyon 20230327 4

The brain is the main oxygen-consuming organ and is vulnerable to ischemic shock or insufficient blood perfusion. Brain hypoxia has a persistent and detrimental effect on resident neurons. Previous studies have identified alterations in genes and metabolites in ischemic brain shock by single omics, but the adaptive systems that neurons use to cope with hypoxia remain uncovered. In the present study, we constructed an acute hypoxia model and performed a multi-omics analysis from RNA-sequencing an ...[more]

PMID: 37025787

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Project description:BackgroundMutations in DYRK1A are a cause of microcephaly, autism spectrum disorder, and intellectual disability; however, the underlying cellular and molecular mechanisms are not well understood.MethodsWe generated a conditional mouse model using Emx1-cre, including conditional heterozygous and homozygous knockouts, to investigate the necessity of Dyrk1a in the cortex during development. We used unbiased, high-throughput phosphoproteomics to identify dysregulated signaling mechanisms in the developing Dyrk1a mutant cortex as well as classic genetic modifier approaches and pharmacological therapeutic intervention to rescue microcephaly and neuronal undergrowth caused by Dyrk1a mutations.ResultsWe found that cortical deletion of Dyrk1a in mice causes decreased brain mass and neuronal size, structural hypoconnectivity, and autism-relevant behaviors. Using phosphoproteomic screening, we identified growth-associated signaling cascades dysregulated upon Dyrk1a deletion, including TrkB-BDNF (tyrosine receptor kinase B-brain-derived neurotrophic factor), an important regulator of ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) and mTOR (mammalian target of rapamycin) signaling. Genetic suppression of Pten or pharmacological treatment with IGF-1 (insulin-like growth factor-1), both of which impinge on these signaling cascades, rescued microcephaly and neuronal undergrowth in neonatal mutants.ConclusionsAltogether, these findings identify a previously unknown mechanism through which Dyrk1a mutations disrupt growth factor signaling in the developing brain, thus influencing neuronal growth and connectivity. Our results place DYRK1A as a critical regulator of a biological pathway known to be dysregulated in humans with autism spectrum disorder and intellectual disability. In addition, these data position Dyrk1a within a larger group of autism spectrum disorder/intellectual disability risk genes that impinge on growth-associated signaling cascades to regulate brain size and connectivity, suggesting a point of convergence for multiple autism etiologies.

Dataset Information

Integrated transcriptomic and metabolomic analysis of cortical neurons reveals dysregulated lipid metabolism, enhanced glycolysis and activated HIF-1 signaling pathways in acute hypoxia.

Publications

Integrated transcriptomic and metabolomic analysis of cortical neurons reveals dysregulated lipid metabolism, enhanced glycolysis and activated HIF-1 signaling pathways in acute hypoxia.

Similar Datasets

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