DNA cytosine methylation by DNA methyltransferases (Dnmts) is a major epigenetic modification which reversibly represses gene expression in vertebrate animals. To investigate the role of DNA methylation in the regulation of genes expressed in the central nervous system (CNS), we use conditional deletion strategies to spatially and temporally restrict the loss of Dnmt1. The conditional mutants generated survive into adulthood; however, upon anatomical inspection, mutant adult brains are strikingly deformed. This proposal aims to define the neural defects observed in the hypomethylated brain regions of our conditional mutant mice. Since DNA methylation is an epigenetic modification involved in transcriptional repression, we hypothesize that DNA hypomethylation leads to improper regulation of gene expression, thus causing disruptions in cortical and hippocampal function and ultimately leading to the death of hypomethylated cells. We will examine the effect of DNA hypomethylation in neuronal survival by: 1. characterizing neural defects of the Emxl-cre; DNMT12lox/2lox mutant brain, and 2. defining the cell death pathway initiated by DNA hypomethylation in the CNS.
|Hutnick, Leah K; Golshani, Peyman; Namihira, Masakasu et al. (2009) DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation. Hum Mol Genet 18:2875-88|