RT Journal Article
SR Electronic
T1 DNA Hypomethylation Perturbs the Function and Survival of CNS Neurons in Postnatal Animals
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 788
OP 797
DO 10.1523/JNEUROSCI.21-03-00788.2001
VO 21
IS 3
A1 Guoping Fan
A1 Caroline Beard
A1 Richard Z. Chen
A1 Györgyi Csankovszki
A1 Yi Sun
A1 Marina Siniaia
A1 Detlev Biniszkiewicz
A1 Brian Bates
A1 Peggy P. Lee
A1 Ralf Kühn
A1 Andreas Trumpp
A1 Chi-Sang Poon
A1 Christopher B. Wilson
A1 Rudolf Jaenisch
YR 2001
UL http://www.jneurosci.org/content/21/3/788.abstract
AB DNA methyltransferase I (Dnmt1), the maintenance enzyme for DNA cytosine methylation, is expressed at high levels in the CNS during embryogenesis and after birth. Because embryos deficient for Dnmt1 die at gastrulation, the role of Dnmt1 in the development and function of the nervous system could not be studied by using this mutation. We therefore used the cre/loxP system to produce conditional mutants that lack Dnmt1 in neuroblasts of embryonic day 12 embryos or in postmitotic neurons of the postnatal animal. Conditional deletion of theDnmt1 gene resulted in rapid depletion of Dnmt1 proteins, indicating that the enzyme in postmitotic neurons turns over quickly. Dnmt1 deficiency in postmitotic neurons neither affected levels of global DNA methylation nor influenced cell survival during postnatal life. In contrast, Dnmt1 deficiency in mitotic CNS precursor cells resulted in DNA hypomethylation in daughter cells. Whereas mutant embryos carrying 95% hypomethylated cells in the brain died immediately after birth because of respiratory distress, mosaic animals with 30% hypomethylated CNS cells were viable into adulthood. However, these mutant cells were eliminated quickly from the brain within 3 weeks of postnatal life. Thus, hypomethylated CNS neurons were impaired functionally and were selected against at postnatal stages.