This study focuses on mutations affecting the nervous system in mice and is designed to increase our understanding of how genes control the development, organization, and maintenance of this extraordinary organ. We plan to construct interspecies chimeras by fusing 8-cell embryos of two species, Mus musculus (the house mouse) and Mus caroli. The cells of each species will be detected in autoradiograms with a radioactive synthesized DNA fragment that binds selectively to satellite DNA of one or the other species, but not both, the method will allow tracing of the clonal history and sorting out of developing nervous system cells. We will also seek to define specific genetic loci that modify either the severity or the apparent dominance-recessive relationships of a disease-causing mutation. The test case is a mouse mutation named Purkinje cell degeneration, pcd, a recessive which causes cerebellar ataxia and progressive visual loss; severity of the disease is increased by another recessive locus linked to pcd on chromosome 13, and it is converted to dominant expression by another locus on chromosome 7 and probably an additional locus; this model may explain some of the puzzles in human inherited disease pedigrees. We will also explore the relationships among various neurons and their target cells in the developing and mature cerebellum, with computer graphics methods for automated 3-D reconstruction of cells, specific ligand autoradiography, and mutant analysis. Finally, we propose to develop critical inbred stocks that will allow quantitative comparisons between mutants, and we will give the first description of a number of new mouse inherited neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020820-06
Application #
3401447
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1974-01-01
Project End
1990-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Rosario, C M; Yandava, B D; Kosaras, B et al. (1997) Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action. Development 124:4213-24
Rosario, C M; Dubovy, P; Sidman, R L et al. (1995) Peripheral target reinnervation following orthotopic grafting of fetal allogeneic and xenogeneic dorsal root ganglia. Exp Neurol 132:251-61
Kozlova, E N; Rosario, C M; Stromberg, I et al. (1995) Peripherally grafted human foetal dorsal root ganglion cells extend axons into the spinal cord of adult host rats by circumventing dorsal root entry zone astrocytes. Neuroreport 6:269-72
Rosario, C M; Aldskogius, H; Carlstedt, T et al. (1993) Differentiation and axonal outgrowth pattern of fetal dorsal root ganglion cells orthotopically allografted into adult rats. Exp Neurol 120:16-31
Shine, H D; Readhead, C; Popko, B et al. (1992) Morphometric analysis of normal, mutant, and transgenic CNS: correlation of myelin basic protein expression to myelinogenesis. J Neurochem 58:342-9
Suter, U; Moskow, J J; Welcher, A A et al. (1992) A leucine-to-proline mutation in the putative first transmembrane domain of the 22-kDa peripheral myelin protein in the trembler-J mouse. Proc Natl Acad Sci U S A 89:4382-6
Green, R C; Seyfried, T N (1991) Kindling susceptibility and genetic seizure predisposition in inbred mice. Epilepsia 32:22-6
Henry, E W; Eicher, E M; Sidman, R L (1991) The mouse mutation claw paw: forelimb deformity and delayed myelination throughout the peripheral nervous system. J Hered 82:287-94
Propst, F; Rosenberg, M P; Cork, L C et al. (1990) Neuropathological changes in transgenic mice carrying copies of a transcriptionally activated Mos protooncogene. Proc Natl Acad Sci U S A 87:9703-7
Shine, H D; Readhead, C; Popko, B et al. (1990) Myelin basic protein and myelinogenesis: morphometric analysis of normal, mutant and transgenic central nervous system. Prog Clin Biol Res 336:81-92

Showing the most recent 10 out of 29 publications