Disruption of the N-catenin Gene in Cerebellar Deficient Folia Mutant Mice Results in Defects in Cerebellar and Hippocampal Lamination and Pavlovian Conditioning

다국어 초록 (Multilingual Abstract)

Positional cloning (map-based cloning) of mutations or genetic variations has been served as an invaluable tool to understand in vivo functions of genes and to identify molecular components underlying phenotypes of interest. Mice homozygous for the cerebellar deficient folia (cdf) mutation are ataxic, with cerebellar hypoplasia and abnormal lobulation of the cerebellum. In the cdf mutant cerebellum approximately 40% of Purkinje cells are ectopically located within the white matter and the inner granule cell layer (IGL). To identify the cdf gene, a high-resolution genetic map for the cdf-gene-encompassing region was constructed using 1997 F2 mice generated from C3H/HeSnJ-cdf/cdf and CAST/Ei intercross. The cdf gene showed complete linkage disequilibrium with three tightly linked markers D6Mit208, D6Mit359, and D6Mit225. A contig using YAC, BAC, and P1 clones was constructed for the cdf critical region to identify the gene. We have identified a deletion in the cdf critical region on Chromosome 6 that removes approximately 150 kb of DNA, including an exon encoding a portion of the actin-binding domain of N-catenin, the protein that links the classical cadherins to the neuronal cytoskeleton. Normal cerebellar and hippocampal morphology was restored in cdf mutant mice expressing an N-catenin cDNA transgene, demonstrating that the catenin/cadherin cell adhesion complexes play an important role in the lamination of the cerebellum and hippocampus. Furthermore, our analysis of mutant mice demonstrates that fear conditioning, a form of associative learning, and prepulse inhibition are disrupted in cdf mutant mice, implicating the involvement of catenin/cadherin complexes in these behavioral processes.

목차 (Table of Contents)

• Abstract
• Phenotypes of cdf mutant mice
• High-resolution genetic mapping of the cdf gene
• Construction of a physical map for a cdf critical region
• Identification of the cdf gene
• Transgenic rescue of cdf mutant mice
• Pavlovian-conditioning defects in cdf mutant mice
• References