Choline deficiency alters neuronal development

Fetal brain development is a complicated process that involves cell proliferation, apoptosis, cell migration and differentiation. These events can be altered by inadequate nutrition, and various nutrient deficiencies can lead to negative outcomes in fetal brain development. To firmly establish the mechanisms responsible for these changes is a prerequisite for a better design of the public health policies, required for the early prevention of inborn defects in the fetal brain development.; Maternal choline deficiency decreases cell proliferation and migration, and increases apoptosis of neuronal progenitors in the developing fetal brain. These outcomes associate with decreased memory in the offspring. The major aim of this dissertation is to establish the scientific bases for a possible mechanism that could explain the changes associated with choline deficiency. We tested the hypothesis that choline is a required nutrient for normal DNA methylation, and that choline deficiency alters the gene-specific methylation patterns required for the normal development of neuronal progenitors.; The present work demonstrates that gene and protein expressions for key regulators of the cell-cycle are altered by choline deficiency, and parallel alterations of global and gene-specific DNA methylation could represent the underlying mechanism that is responsible for these changes. Our in vivo and in vitro studies show that increased expression of cyclin-dependent kinase inhibitors (negative regulators of cell proliferation) is associated with decreased cell proliferation. We also report novel findings regarding the effects of choline deficiency on expression patterns of other genes involved in neuronal differentiation, apoptosis, and calcium-binding.; In summary, choline deficiency alters gene expression in neuronal progenitors. The relationship between gene expression and alterations in DNA methylation suggests that choline modulates the epigenetic regulation of gene expression, with important consequences for brain development during fetal life.