Human Molecular Genetics Advance Access originally published online on May 10, 2009
Human Molecular Genetics 2009 18(15):2875-2888; doi:10.1093/hmg/ddp222
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation
1 Department of Human Genetics 2 Department of Neuroscience Interdepartmental Program, David Geffen School of Medicine, University of California at Los Angeles, 695 Charles Young Drive South, Los Angeles, CA 90095, USA 3 Department of Neurobiology 4 Department of Neurology 5 Department of Psychiatry and Behavioral Sciences 6 Department of Psychology, UCLA, Los Angeles, CA 90095, USA
* To whom correspondence should be addressed. Tel: +1 3102670439; Fax: +1 3107945446; Email: gfan{at}mednet.ucla.edu
Received February 27, 2009; Revised April 18, 2009; Accepted May 6, 2009
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 
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.