DNA methylation is a major epigenetic factor involved in gene regulation, genomic imprinting, and X-chromosome inactivation. Aberrant DNA methylation has been associated with several human mental retardation disorders including Rett, ICF, Fragile-X, and ATRX syndromes. However, little is known about how DNA methylation changes perturb neural function and lead to neurological disorders. The long-term objective of our research is to elucidate the role of DNA methylation in neural development and function. Using the conditional gene knockout approach, we have recently constructed a strain of mutant mice in which the maintenance methyltransferase gene Dnmtl is deleted exclusively in precursor cells of the central nervous system (CNS). Dnmtl deficiency in CNS precursor cells causes significant demethylation in differentiating neurons and glial cells. Mutant embryos carrying 95 percent of hypomethylated CNS cells die immediately after birth, indicating that hypomethylation disrupts vital CNS function for animal survival. In mosaic animals carrying 30 percent of Dnmtl-/- cells in the embryonic CNS, mutant cells are selectively eliminated during postnatal maturation, showing that methylation is also important for the survival of postnatal CNS cells. The goal of this proposal is to characterize the neural defects in the hypomethylated brain and define the molecular mechanism by which DNA hypomethylation influences the survival and differentiation of neurons and glia. Our working hypothesis is that DNA hypomethylation results in inappropriate expression of many neural genes, which subsequently leads to multiple defects during CNS development. We therefore propose the following Specific Aims: 1. To determine the effect of DNA hypomethylation on the cell fate determination of CNS precursor cells. 2. To determine whether DNA hypomethylation affects neuronal maturation and synaptic function. 3. To define the mechanism of cell death triggered by DNA hypomethylation in the postnatal CNS environment. The proposed study may provide fundamental insights into the role of DNA methylation in neural development as well as the disease mechanism underlying certain mental retardation disorders.
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