The genetic and epigenetic mechanisms by which the brain develops into a highly ordered structure are largely unknown. The goal of this proposal is to elucidate some of the early postmitotic events in neurogenesis. There are several neurological mouse mutants which are defective in particular aspects of this developmental program. Two such genetic mutants, the weaver (wv) and the reeler (rl), hold forth fascinating information concerning the genetic control over the migratory phase of neurogenesis. These mutations affect the ability of a single cell type (the wv cerebellar granule cells) or virtually all cell types (rl) to migrate and stabilize appropriately. Experimental mouse chimeras provide a direct means to ascertain the target(s) of mutant gene action. Four cell embryos of normal (Mus caroli) and neurological mutant (Mus musculus) mice will be aggregated to form a single chimeric embryo composed of genetically normal and mutant cells. A new cell marking system will be used to identify each cell of the chimeric brain, as genotypically normal or mutant. This new cell marker, which involves the in situ hybridization of a species-specific cDNA probe to mark Mus musculus but not Mus caroli cells, will permit careful light and electron microscopic analyses of each cell's genotype compared to its phenotype. The genotype/phenotype comparisons will define the intrinsic or extrinsic nature of wv and rl mutant gene action relative to all cell types in the cerebellum. This type of information will provide a better understanding of normal brain development and how abnormal development occurs at both the more obvious (e.g., congenital ataxias) and more subtle (e.g., mental retardation) levels of dysgenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023475-03
Application #
3407003
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
McAndrew, P E; Frostholm, A; Evans, J E et al. (1998) Novel receptor protein tyrosine phosphatase (RPTPrho) and acidic fibroblast growth factor (FGF-1) transcripts delineate a rostrocaudal boundary in the granule cell layer of the murine cerebellar cortex. J Comp Neurol 391:444-55
Goldowitz, D; Cushing, R C; Laywell, E et al. (1997) Cerebellar disorganization characteristic of reeler in scrambler mutant mice despite presence of reelin. J Neurosci 17:8767-77
Mullen, R J; Hamre, K M; Goldowitz, D (1997) Cerebellar mutant mice and chimeras revisited. Perspect Dev Neurobiol 5:43-55
Hemre, K M; Keller-Peck, C R; Campbell, R M et al. (1996) Annexin IV is a marker of roof and floor plate development in the murine CNS. J Comp Neurol 368:527-37
Surmeier, D J; Mermelstein, P G; Goldowitz, D (1996) The weaver mutation of GIRK2 results in a loss of inwardly rectifying K+ current in cerebellar granule cells. Proc Natl Acad Sci U S A 93:11191-5
Hamre, K M; Goldowitz, D (1996) Analysis of gene action in the meander tail mutant mouse: examination of cerebellar phenotype and mitotic activity of granule cell neuroblasts. J Comp Neurol 368:304-15
Hamre, K M; Chepenik, K P; Goldowitz, D (1995) The annexins: specific markers of midline structures and sensory neurons in the developing murine central nervous system. J Comp Neurol 352:421-35
Smeyne, R J; Goldowitz, D (1990) Purkinje cell loss is due to a direct action of the weaver gene in Purkinje cells: evidence from chimeric mice. Brain Res Dev Brain Res 52:211-8
Smeyne, R J; Goldowitz, D (1990) Postnatal development of the wild-type and weaver cerebellum after embryonic administration of propylthiouracil (PTU). Brain Res Dev Brain Res 54:282-6
Goldowitz, D; Barthels, D; Lorenzon, N et al. (1990) NCAM gene expression during the development of cerebellum and dentate gyrus in the mouse. Brain Res Dev Brain Res 52:151-60

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