Neural development is composed of a cascade of genetic programs that precisely control stage-specific gene activities required for neural patterning, cell migration and neuronal connectivity. Recent studies indicate that the temporally- and spatially-controlled gene expression in the nervous system is not only regulated by the transcriptional machinery, but also subject to modulation by epigenetic mechanisms such as DNA methylation and chromatin remodeling. DNA methylation is catalyzed by a family of DNA methyltransferases (Dnmts) that include de novo
(Dnmt3a and Dnmt3b) and maintenance methyltransferases (Dnmt1) (1
). All three enzymes are expressed in the central nervous system (CNS) and are dynamically regulated during development and differentiation (4
). Mechanistically, DNA methylation inhibits gene expression by either directly interfering with transcription factor binding to DNA (6
) or recruitment of methyl CpG binding proteins (MBDs) which complex with co-repressor(s) and histone modification enzymes such as histotone deacetylases and methyltransferases to transform chromatin to a repressive state (reviewed in 5
The important role for DNA methylation in CNS development and function is first implicated by the identification of MeCP2 mutations in mental retardation disorder Rett syndrome (8
). As a prototype of the MBD proteins, MeCP2 is highly expressed in post-mitotic neurons and is involved in regulating neuronal gene expression including neurotrophin BDNF and transcription factor Dlx5/6 (9
). MeCP2-deficient mice exhibit many typical Rett phenotypes including neuronal atrophy and stereotypic symptom such as irregular breathing pattern (12
). To directly examine the role of DNA methylation in the CNS, we have previously created a mouse model with DNA hypomethylation in the entire developing CNS (14
). By conditional deletion of Dnmt1
in neural precursor cells, we demonstrated that DNA hypomethylation in the CNS disrupts neural control of breathing at birth, leading to neonatal lethality of mutant mice (14
). Furthermore, DNA hypomethylation in neural precursor/stem cells triggers precocious glial differentiation by activating the JAK-STAT pathway and the expression of glial marker genes such as glial fibrillary acidic protein (Gfap
). Thus, DNA methylation serves as a key epigenetic mechanism in the temporal control of neural stem cell differentiation.
In the current study, we attempted to address the role of DNA methylation during cortical neuronal maturation at the perinatal stages. We have crossed the Emx1-cre
) with the Dnmt1 conditional allele (Dnmt12lox
) to generate a strain of Dnmt1 mutant mice that are viable in adulthood but exhibit DNA hypomethylation exclusively in the dorsal forebrain. Although mutant mice have a normal lifespan, they develop cortical degeneration during early postnatal development and show obvious behavioral defects such as hyperactivity and impaired learning and memory. Surprisingly, a significant portion of hypomethylated cortical neurons was retained in the mutant brain, allowing us to address the effect of DNA hypomethylation on neural gene expression and the maturation of cortical neurons postnatally.