This project will use recombinant DNA probes for individual species of mRNA to study morphogenesis and cytodifferentiation in the developing mouse cerebellum. By examining the cellular distribution and the temporal pattern of individual gene expression in normal and mutant mice, we will evaluate four hypotheses: (1) The five types of neuron of the mature cerebellum express sets of genes that only partially overlap, both during cytodifferentiation and in the fully differentiated state; (2) individual neuron types are most likely to differ in the particular species of messenger RNAs that accumulate to high or moderate concentrations; (3) genes for glutamic acid decarboxylase are expressed at different times in four of the five neuron types; and (4) neuroblasts in the two germinal layers that give rise to the five cerebellar neuron types do not begin to express cell type specific genes until they start their characteristic migrations into new microenvironments. The preparation of probes for mRNAs preferentially expressed in individual neuron types will also allow the examination of a further hypothesis concerning hereditary ataxias both in mice and humans - that the molecular lesions in these conditions are located in genes that are preferentially expressed in the affected cell types. This hypothesis will be tested for four cerebellar mouse mutants whose primary defects appear to be in Purkinje cell development. We will also search for changes in the structure of cerebellum-specific genes in humans with hereditary ataxias. This project will provide basic information about the expression of specific genes during the development of a region of the brain that has been extremely well studied from morphological, physiological and genetic perspectives. If the proposed hypotheses about the molecular lesions in murine and human hereditary ataxias are correct, this work will also lead to a direct approach to diagnosis, and future therapies, for human neurogenetic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020356-03
Application #
3400685
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1983-12-01
Project End
1986-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Frantz, G D; Wuenschell, C W; Messer, A et al. (1996) Presence of calbindin D28K and GAD67 mRNAs in both orthotopic and ectopic Purkinje cells of staggerer mice suggests that staggerer acts after the onset of cytodifferentiation. J Neurosci Res 44:255-62
Frantz, G D; Tobin, A J (1994) Cellular distribution of calbindin D28K mRNAs in the adult mouse brain. J Neurosci Res 37:287-302
Hendrickson, A E; Tillakaratne, N J; Mehra, R D et al. (1994) Differential localization of two glutamic acid decarboxylases (GAD65 and GAD67) in adult monkey visual cortex. J Comp Neurol 343:566-81
Esclapez, M; Tillakaratne, N J; Kaufman, D L et al. (1994) Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci 14:1834-55
Feldblum, S; Erlander, M G; Tobin, A J (1993) Different distributions of GAD65 and GAD67 mRNAs suggest that the two glutamate decarboxylases play distinctive functional roles. J Neurosci Res 34:689-706
Kim, H Y; Sapp, D W; Olsen, R W et al. (1993) GABA alters GABAA receptor mRNAs and increases ligand binding. J Neurochem 61:2334-7
Esclapez, M; Tillakaratne, N J; Tobin, A J et al. (1993) Comparative localization of mRNAs encoding two forms of glutamic acid decarboxylase with nonradioactive in situ hybridization methods. J Comp Neurol 331:339-62
Tillakaratne, N J; Erlander, M G; Collard, M W et al. (1992) Glutamate decarboxylases in nonneural cells of rat testis and oviduct: differential expression of GAD65 and GAD67. J Neurochem 58:618-27
Mercugliano, M; Soghomonian, J J; Qin, Y et al. (1992) Comparative distribution of messenger RNAs encoding glutamic acid decarboxylases (Mr 65,000 and Mr 67,000) in the basal ganglia of the rat. J Comp Neurol 318:245-54
Bu, D F; Erlander, M G; Hitz, B C et al. (1992) Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. Proc Natl Acad Sci U S A 89:2115-9

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