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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD009172-23
Application #
2403055
Study Section
Special Emphasis Panel (NSS)
Program Officer
Tasca, Richard J
Project Start
1978-05-01
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1999-04-30
Support Year
23
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Kim, D S; Szczypka, M S; Palmiter, R D (2000) Dopamine-deficient mice are hypersensitive to dopamine receptor agonists. J Neurosci 20:4405-13
Szczypka, M S; Rainey, M A; Palmiter, R D (2000) Dopamine is required for hyperphagia in Lep(ob/ob) mice. Nat Genet 25:102-4
Cho, M C; Rao, M; Koch, W J et al. (1999) Enhanced contractility and decreased beta-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine. Circulation 99:2702-7
Szczypka, M S; Mandel, R J; Donahue, B A et al. (1999) Viral gene delivery selectively restores feeding and prevents lethality of dopamine-deficient mice. Neuron 22:167-78
Commins, S P; Marsh, D J; Thomas, S A et al. (1999) Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue. Endocrinology 140:4772-8
Szczypka, M S; Rainey, M A; Kim, D S et al. (1999) Feeding behavior in dopamine-deficient mice. Proc Natl Acad Sci U S A 96:12138-43
Szczypka, M S; Zhou, Q Y; Palmiter, R D (1998) Dopamine-stimulated sexual behavior is testosterone dependent in mice. Behav Neurosci 112:1229-35
Thomas, S A; Marck, B T; Palmiter, R D et al. (1998) Restoration of norepinephrine and reversal of phenotypes in mice lacking dopamine beta-hydroxylase. J Neurochem 70:2468-76
Tafari, A T; Thomas, S A; Palmiter, R D (1997) Norepinephrine facilitates the development of the murine sweat response but is not essential. J Neurosci 17:4275-81
Thomas, S A; Palmiter, R D (1997) Impaired maternal behavior in mice lacking norepinephrine and epinephrine. Cell 91:583-92

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