DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation
Open accessAbstract
DNA methylation is a major epigenetic factor regulating genome reprogramming, cell differentiation and developmental gene expression. To understand the role of DNA methylation in central nervous system (CNS) neurons, we generated conditional Dnmt1 mutant mice that possess approximately 90% hypomethylated cortical and hippocampal cells in the dorsal forebrain from E13.5 on. The mutant mice were viable with a normal lifespan, but displayed severe neuronal cell death between E14.5 and three weeks postnatally. Accompanied with the striking cortical and hippocampal degeneration, adult mutant mice exhibited neurobehavioral defects in learning and memory in adulthood. Unexpectedly, a fraction of Dnmt1(-/-) cortical neurons survived throughout postnatal development, so that the residual cortex in mutant mice contained 20-30% of hypomethylated neurons across the lifespan. Hypomethylated excitatory neurons exhibited multiple defects in postnatal maturation including abnormal dendritic arborization and impaired neuronal excitability. The mutant phenotypes are coupled with deregulation of those genes involved in neuronal layer-specification, cell death and the function of ion channels. Our results suggest that DNA methylation, through its role in modulating neuronal gene expression, plays multiple roles in regulating cell survival and neuronal maturation in the CNS.
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The establishment, maintenance, and removal of epigenetic marks are critical during neurodevelopment, and when disrupted can have significant impacts on neurodevelopment and cognitive function.
“The establishment, maintenance, and removal of epigenetic marks are critical during neurodevelopment and when disrupted can have significant impacts on neurodevelopment and cognitive function [ 63–66 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [63]
Conditional deletion of Dnmt1 in developing excitatory neurons and astroglia of the mouse cortex and hippocampus results in neuronal cell death between GD14.5 to 3 weeks postnatally and results in deficits in learning and memory in adulthood.
“Conditional deletion of Dnmt1 in developing excitatory neurons and astroglia of the mouse cortex and hippocampus results in neuronal cell death between GD14.5 to 3 weeks postnatally and results in deficits in learning and memory in adulthood [ 63 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [63]
A fraction of hypomethylated neurons survive postnatally but exhibit increased dendritic branching and impaired excitability.
“A fraction of hypomethylated neurons survive postnatally but exhibit increased dendritic branching and impaired excitability, likely through mechanisms related to neuronal layer specification, cell death, and ion channel function [ 63 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [63]
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- Authors
- Hutnick, L. K., Golshani, P., Namihira, M., Xue, Z., Matynia, A., Yang, X. W., Silva, A. J., Schweizer, F. E., & Fan, G.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Fan, Guoping
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-05-10
- Volume
- 18
- Issue
- 15
- Pages
- 2875-2888
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2706688
- OpenAlex
- W2107498593
- Cited by
- 181
- References
- 51
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 8 · 2023: 8 · 2022: 6 · 2021: 7 · 2020: 13 · 2019: 10 · 2018: 13 · 2017: 12 · 2016: 17 · 2015: 13 · 2014: 14 · 2013: 14 · 2012: 11
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- Achievement Rewards for College Scientists Foundation
- National Institutes of Health (5f31ns051005-03)
- National Institute of Neurological Disorders and Stroke (5F31NS051005, R01NS051411)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- DNA methylation, DNA hypomethylation, DNMT1, conditional knockout mice, forebrain, cortical degeneration, hippocampus, neuronal maturation, neuronal cell death, dendritic branching, neuronal excitability, learning and memory impairment, ion channels, epigenetics
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, Animals, Cerebral Cortex, DNA (Cytosine-5-)-Methyltransferases, Hippocampus, Neurons, Prosencephalon, Mice, Knockout, DNA Methylation, Mice, Neurogenesis
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