Wnt-signaling pathways are dysregulated in female cerebellum following an early methyl donor deficiency in a rat nutritional model
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PROVIDER: PRJNA411842 | ENA |
REPOSITORIES: ENA
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Project description:Early methyl donor –especially B9 and B12 vitamins- deficiency (MDD) is involved in birth defects and brain development retardation. Molecular mechanisms that take place in response to MDD still remain not well understood. In this study we took advantage of a rat nutritional MDD model and performed a microarray analysis on female cerebellum, in order to identify which genes and molecular pathways are disrupted in response to MDD. We found that cerebellum development is altered, with a decrease of the granular cell layer thickness in cerebellum at P21. Furthermore, we investigated the involvement of Wnt-signaling pathway –a major molecular pathway involved in neuronal development but also later in synaptic assembly and neurotransmission. We found that Wnt canonical and Ca2+ pathways are disrupted following early MDD. Notably, we identified GSK3β as a pivotal player affected by MDD, affecting synaptic assembly and signaling. These results could explain the structural brain defects previously observed in response to early MDD and identify new genes and a new molecular pathway that is affected following nutritional methyl donor deprivation.
2018-05-11 | GSE104164 | GEO
Project description:Fetal alcohol exposure at any stage of pregnancy can lead to Fetal Alcohol Spectrum Disorder (FASD), a group of life-long conditions characterized by congenital malformations, as well as cognitive, behavioral, and emotional impairments. The teratogenic effects of alcohol have long been publicized; yet fetal alcohol exposure is one of the most common preventable causes of birth defects. Currently, alcohol abstinence during pregnancy is the best and only way to prevent FASD. However, alcohol consumption remains astoundingly prevalent among pregnant women; therefore, additional measures need to be made available to help protect the developing embryo before irreparable damage is done. Maternal nutritional interventions using methyl donors have been investigated as potential preventative measures to mitigate the adverse effects of fetal alcohol exposure. Here, we show that a single acute preimplantation (E2.5; 8-cell stage) fetal alcohol exposure in mice leads to long-term FASD-like morphological phenotypes (e.g., growth restriction, brain malformations, skeletal delays) in late-gestation embryos (E18.5) and demonstrate that supplementing the maternal diet with a combination of four methyl donor nutrients, folic acid, choline, betaine, and vitamin B12, prior to conception and throughout gestation effectively reduces the incidence and severity of alcohol-induced morphological defects without altering DNA methylation status and regulation of imprinting control regions. This study clearly supports that preimplantation embryos are vulnerable to the teratogenic effects of alcohol, emphasizing the dangers of maternal alcohol consumption during early gestation, and provides a potential proactive maternal nutritional intervention to minimize FASD progression, reinforcing the importance of adequate preconception and prenatal nutrition.
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Project description:DNA methylation was assessed in genomic DNA obtained from the arcuate nucleus of heifers fed to gain body weight at high (HG, n = 4) and low (LG, n = 4) rates from 4.5 to 8.5 mo of age. A methyl-CpG binding domain-based (MBD) protein assay was performed to capture fragments of methylated DNA (methylated-enriched DNA). Input (total) and methylated-enriched DNA were labeled with two different dyes and co-hybridized to a custom-designed oligonucleotide array targeted to genes associated with nutritional inputs and the control of puberty. The ratio of the log2 (enriched/input) of the normalized intensities, were determined. Data was analyzed comparing values of HG versus LG heifers. Two nutritional schedules: HG (n=4 heifers) and LG (n=4 heifers); one array per heifer; methylated enriched DNA (enriched) and total DNA (input) co-hybridyzed into each array Methylated-enriched DNA obtained from a methyl-CpG binding domain-based (MBD) protein assay
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Project description:Expression profiles of normal colons in ApcMin mice that were fed methyl deficient diet for 11 weeks vs controls Expression profiles of normal colons in ApcMin mice that were fed methyl deficient diet for 11 weeks vs controls fed methyl donor sufficient diets
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Project description:Evaluation of transgenerational influence of paternal dietary methyl substrates on offspring and grand-offspring brain and behavior Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (MD F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. These phenomena did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.
2017-04-20 | GSE90499 | GEO
Project description:Evaluation of transgenerational influence of paternal dietary methyl substrates on offspring and grand-offspring brain and behavior Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (MD F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. These phenomena did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.
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Project description:Expression profiles of normal colons in ApcMin mice that were fed methyl deficient diet for 11 weeks vs controls
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Project description:Transcriptome analysis of Ts1Cje (mouse model of Down syndrome) and euploids murine cerebellum during postnatal development Keywords = Down syndrome Keywords = Chromosome 21 Keywords = Transcriptome Keywords = Microarray Keywords = Cerebellum Keywords = Development Keywords: other
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