Genetic modifiers of cerebellar hypoplasia in Zfp423-deficient mice.

摘要

The cerebellum plays a critical role in the neural functions of both humans and mice, sustaining a significant control over motor, coordination, and proprioception. Despite its small size, the cerebellum comprises over 50% of all neurons in the brain. Therefore, malformation or lesion of the cerebellum, although not fatal, may cause a severe handicap to both physical and mental functions. This thesis describes the design, implementation, and results of two genome-wide linkage studies to detect genetic modifiers of cerebellum defects in mice that lack the zinc finger transcription factor Zfp423. We find significant linkage peaks at chromosome 3 (LOD = 4.74) and 17 (LOD = 4.67), along with a suggestive linkage on chromosome 15 (LOD = 3.23) in a scan of 222 BALBx129 F2 Zfp323nur12 mutant mice, showing a clear genetic basis for phenotypic differences among mutant mice. In a second study of 132 BALBxB6 F2 Zfp323nur12 mutants, chromosome 4 (LOD = 3.69) shows nominally significant results that may embed one or more modifiers. This thesis also includes the breeding of congenic mice toward an attempt to narrow and isolate the possible candidate genes in the 129 mouse strain.