In mammals DNA cytosine methylation is one of the major epigenetic factors that regulate many cellular events including developmental gene expression and genomic imprinting. Alternations in DNA methylation machinery have been linked to several mental retardation disorders, including Rett, ICF, Fragile-X, and ATRX syndromes, suggesting that methylation is important for neuronal development and function. To investigate the function of DNA methylation in the central nervous system (CNS), we have recently applied the cre/loxP system to delete the maintenance DNA methyltransferase Dnmtl gene exclusively in the CNS. By crossing the Emx1-cre transgene with the Dnmtl conditional allele (Dnmt2lox), we have obtained conditional knockout mice with Dnmtl deficiency restricted to the cortex and hippocampus. Emx1-cre mediated Dnmtl gene deletion is initiated in pallial cortical precursor cells at embryonic day (E) 9-10, resulting in DNA hypomethylation in embryonic and postnatal cortical projection neurons. Mutant mice are viable in adulthood but exhibit obvious behavioral defects such as hyperactivity and hind limb clasping upon tail suspension. Morphological studies indicate that Emx1-cre; Dnmtl mutant mice exhibit massive loss of cortical volume, thus become a valuable animal model for studying the effect of DNA hypomethylation on cortical degeneration. In this proposal, we plan to first examine the time course of cortical neuronal cell death and determine the gross histological and behavioral defects in the mutant mice. Further experiments are designed to determine the effect of DNA hypomethylation on the proliferation and differentiation of precursor cells, as well as dendritic arborization of Dnmtl-/- neurons. Finally, we plan to determine the mechanism by which DNA hypomethylation induces neuronal cell death in the mutant cortex. It is known that levels of DNA methylation decrease with aging and in age-related neurodegenerative disorders such as Alzheimer's disease. Understanding the mechanism of cell death in hypomethylated cortical neurons may help us develop therapeutic strategies to prevent hypomethylation-induced neuronal degeneration. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051411-04
Application #
7367880
Study Section
Special Emphasis Panel (ZRG1-BDCN-D (91))
Program Officer
Sutherland, Margaret L
Project Start
2005-03-15
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$338,768
Indirect Cost
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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