Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain
Prenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those...
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MDPI AG
2024-03-01
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| Online Access: | https://www.mdpi.com/2073-4409/13/5/440 |
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| author | Yanping Huang George R. Flentke Olivia C. Rivera Nipun Saini Sandra M. Mooney Susan M. Smith |
| author_facet | Yanping Huang George R. Flentke Olivia C. Rivera Nipun Saini Sandra M. Mooney Susan M. Smith |
| author_sort | Yanping Huang |
| collection | DOAJ |
| description | Prenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those processes are targeted by alcohol is unknown. Pregnant C57BL/6J mice received 3 g alcohol/kg daily at E8.5–E17.5. Transcriptome sequencing was performed on the E17.5 fetal cortex. Additionally, primary neural stem cells (NSCs) were isolated from the E14.5 cerebral cortex and exposed to alcohol to evaluate nucleolar stress and p53/MDM2 signaling. Alcohol suppressed KEGG pathways involving ribosome biogenesis (rRNA synthesis/processing and ribosomal proteins) and genes that are mechanistic in ribosomopathies (<i>Polr1d</i>, <i>Rpl11</i>; <i>Rpl35</i>; <i>Nhp2</i>); this was accompanied by nucleolar dissolution and p53 stabilization. In primary NSCs, alcohol reduced rRNA synthesis, caused nucleolar loss, suppressed proliferation, stabilized nuclear p53, and caused apoptosis that was prevented by dominant-negative p53 and MDM2 overexpression. Alcohol’s actions were dose-dependent and rapid, and rRNA synthesis was suppressed between 30 and 60 min following alcohol exposure. The alcohol-mediated deficits in ribosomal protein expression were correlated with fetal brain weight reductions. This is the first report describing that pharmacologically relevant alcohol levels suppress ribosome biogenesis, induce nucleolar stress in neuronal populations, and involve the ribosomal/MDM2/p53 pathway to cause growth arrest and apoptosis. This represents a novel mechanism of alcohol-mediated neuronal damage. |
| first_indexed | 2024-04-25T00:33:13Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-04-25T00:33:13Z |
| publishDate | 2024-03-01 |
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| series | Cells |
| spelling | doaj.art-417bc7ba4fdc44fea223c6e62aa833be2024-03-12T16:41:44ZengMDPI AGCells2073-44092024-03-0113544010.3390/cells13050440Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal BrainYanping Huang0George R. Flentke1Olivia C. Rivera2Nipun Saini3Sandra M. Mooney4Susan M. Smith5UNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USAUNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USAUNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USAUNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USAUNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USAUNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USAPrenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those processes are targeted by alcohol is unknown. Pregnant C57BL/6J mice received 3 g alcohol/kg daily at E8.5–E17.5. Transcriptome sequencing was performed on the E17.5 fetal cortex. Additionally, primary neural stem cells (NSCs) were isolated from the E14.5 cerebral cortex and exposed to alcohol to evaluate nucleolar stress and p53/MDM2 signaling. Alcohol suppressed KEGG pathways involving ribosome biogenesis (rRNA synthesis/processing and ribosomal proteins) and genes that are mechanistic in ribosomopathies (<i>Polr1d</i>, <i>Rpl11</i>; <i>Rpl35</i>; <i>Nhp2</i>); this was accompanied by nucleolar dissolution and p53 stabilization. In primary NSCs, alcohol reduced rRNA synthesis, caused nucleolar loss, suppressed proliferation, stabilized nuclear p53, and caused apoptosis that was prevented by dominant-negative p53 and MDM2 overexpression. Alcohol’s actions were dose-dependent and rapid, and rRNA synthesis was suppressed between 30 and 60 min following alcohol exposure. The alcohol-mediated deficits in ribosomal protein expression were correlated with fetal brain weight reductions. This is the first report describing that pharmacologically relevant alcohol levels suppress ribosome biogenesis, induce nucleolar stress in neuronal populations, and involve the ribosomal/MDM2/p53 pathway to cause growth arrest and apoptosis. This represents a novel mechanism of alcohol-mediated neuronal damage.https://www.mdpi.com/2073-4409/13/5/440apoptosisfetal alcohol spectrum disorderneural stem cellsnucleolar stressMDM2p53 |
| spellingShingle | Yanping Huang George R. Flentke Olivia C. Rivera Nipun Saini Sandra M. Mooney Susan M. Smith Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain Cells apoptosis fetal alcohol spectrum disorder neural stem cells nucleolar stress MDM2 p53 |
| title | Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain |
| title_full | Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain |
| title_fullStr | Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain |
| title_full_unstemmed | Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain |
| title_short | Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain |
| title_sort | alcohol exposure induces nucleolar stress and apoptosis in mouse neural stem cells and late term fetal brain |
| topic | apoptosis fetal alcohol spectrum disorder neural stem cells nucleolar stress MDM2 p53 |
| url | https://www.mdpi.com/2073-4409/13/5/440 |
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