TRANSGENIC APPROACHES TO NERVOUS SYSTEM DEVELOPMENT

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Transgenic mice offer a new approach to attack complex systems such as the nervous system. A multi-faceted approach directed towards studying the consequences of interfering with neuron development and function is being developed. As first step, the four genes encoding the enzymes involved in catecholamine biosynthesis will be cloned in order to characterize the neuron- specific enhancer and promoter elements in each of these genes. To help understand the DNA elements that allow expression of these genes in subsets of neurons, the enhancers from the neuron- specific enolase gene, that is expressed in all neurons, will also be characterized. The enhancer/promoter elements from these genes will be used to direct the expression of various structural genes to specific neurons and adrenal medullary cells of transgenic mice. Structural genes will be chosen that may affect various aspects of neuronal cell development or function. They fall into several categories. (i) Oncogenes: The effect of SV40 T- antigen, ras, myc and /or src on neuronal differentiation or transformation will be studied. (ii) Nerve growth factor (NGF): The hypothesis that neuronal growth, differentiation and survival are influenced by gradients of NGF will be tested. (iii) Neurotransmitters: Transgenic mice in which specific subsets of neurons express additional neurotransmitters or neuromodulatory peptides will be created to determine whether altering neurotransmitter synthesis affects the development and function of the nervous system. (iv) Diphtheria toxin: This toxin will be used to ablate epinephrine-producing adrenal medullary cells to study the role of epinephrine in stress response. It will also be used to study the consequences of deleting neurons making a specific neurotransmitter on the development of the rest of the nervous system.