The basic questions which this project is dealing with concern the genetic and epigenetic control mechanisms which specify the numbers and types of cells that are destined to interact in the mature cerebellum. A hypothesis that cerebellar Purkinje cells control both the onset and cessation of proliferation of cells in the external granule layer, mediate the timing signals of hormones, and signal the onset of some differentiated functions in both neurons and glial cells is tested using neurological mutants which exhibit degeneration of Purkinje cells and/or granule cells, congenital hypothyroid mutants, and cerebellar cells in culture. The general approach is to go back and forth between cell cultures and mutants, using the former to examine effects of signals on isolated cells, and interactions between more limited cell populations and cell type ratios than can be found in vivo. The mutants serve as sources of defined, reproducible perturbations of the developing system in vivo, and can be used to generate hypotheses which can then be further tested in vitro. This combination of studies at several levels allows a long-term goal of integrating these cerebellar events with more general chains of developmental events as the more primary effects of the mutations are examined. Specific experiments proposed examine the role of Purkinje cell signals vs. (or in conjunction with) hormonal signals, and interactions with other developing cell types, both in vitro and in vivo. The basic knowledge gained about cell interactions and hormone signaling should be applicable to brain areas other than the cerebellum. Clinically, cerebellar dysfunction in hypothyroidism is an important problem even with current early detection and treatment regimens, and knowledge of a mechanism of action in a hereditary neurodegenerative disease may be of value in understanding human counterparts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS017633-04A1
Application #
3397691
Study Section
Neurology C Study Section (NEUC)
Project Start
1981-09-01
Project End
1988-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
New York State Department of Health
Department
Type
DUNS #
002436061
City
Menands
State
NY
Country
United States
Zip Code
12204
Messer, A; Eisenberg, B; Plummer, J (1991) The Lurcher cerebellar mutant phenotype is not expressed on a staggerer mutant background. J Neurosci 11:2295-302
Messer, A; Plummer-Siegard, J; Eisenberg, B (1990) Staggerer mutant mouse Purkinje cells do not contain detectable calmodulin mRNA. J Neurochem 55:293-302
Wuenschell, C W; Messer, A; Tobin, A J (1990) Lurcher Purkinje cells express glutamic acid decarboxylase and calbindin mRNAs. J Neurosci Res 27:65-70
Eisenberg, B; Messer, A (1989) Tonic/clonic seizures in a mouse mutant carrying the weaver gene. Neurosci Lett 96:168-72
Messer, A; Eisenberg, B; Martin, D L (1989) Effects of mild hyperthyroidism on levels of amino acids in the developing Lurcher cerebellum. J Neurogenet 5:77-85
Messer, A (1988) Thyroxine injections do not cause premature induction of thymidine kinase in sg/sg mice. J Neurochem 51:888-91
Brugge, J S; Lustig, A; Messer, A (1987) Changes in the pattern of expression of pp60c-src in cerebellar mutants of mice. J Neurosci Res 18:532-8