While abundant studies have begun to elucidate ontogeny of the peripheral nervous system, molecular mechanisms underlying brain development remain obscure. This is due in part to the complexity and inaccessibility of the central nervous system (CNS), particularly in developing animals. We, however, are now able to approach questions of developmental regulation in the CNS. We have succeeded in growing brain nuclei in an accessible tissue culture environment and are able to couple study of these nuclei in vitro with sensitive biochemical and morphological techniques. We can thus define molecular events associated with central neuron development. In particular, we have cultured the brain noradrenergic nucleus locus coeruleus. In culture locus neurons express a variety of noradrenergic traits, including endogenous catecholamine (CA), the specific uptake mechanism for norepinephrine (NE) and the CA biosynthetic enzymes, tyrosine hydroxylase and dopamine-Beta-hydroxylase. We thus can use these CA traits to define factors that regulate development of central neurons and determine whether similar rules govern central and peripheral ontogeny. Influences we will study include those of presynaptic depolarizing agents and target tissues. In addition, we will determine the role of glucocorticoids in expression of NE characters. Finally, we will compare regulation of expression of dopamine characters in developing substantia nigra with expression of noradrenergic characters in the locus. These experiments hopefully will provide insight into sites where changes in the normal milieu of a maturing neuron may lead to abnormal brain development. Such an understanding may eventually lead to new therapeutic approaches to congenital birth defects, such as mental retardation and neural tube defects.
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