International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

H19. ENU Induced Behavioral Mouse Mutants that may Involve APP or PrP

Dennis A. Stephenson1,2, Julie Gilchrist1, Dionne Peterson1, Sherry Turner1, Corike Nuibe1 and George A. Carlson1.
1McLaughlin Research Institute, 1520 23rd Street South, Great Falls MT 59405, USA
2Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110 USA

Induction of mutations that contribute to a phenotype (by enhancement or alleviating a characteristic) has proven to be highly effective in dissecting pathways that affect developmental processes in Drosophila melanogaster. Given this success with Drosophila, we have undertaken a mutagenesis programme to identify mutations at loci that might exasperate the mild phenotypic defects associated with 'knock-out' mutants at either the amyloid beta (A4) precursor protein or prion protein locus. Offspring from ENU (ethyl nitrosourea) treated male mice were subjected to a serious of simple behavioral and observational screens. To date, we have screened in excess of 1500 G1 progeny and observed sixteen heritable mutations. Three involved mutations at the tyrosinase (albino) locus providing an estimate of mutation frequency consistent with published data. Several exhibited gait abnormalities while other displayed reduced body weight. Two abnormal gait mutants (lines 67 and 81) exhibit phenotypic variations that appear to depend upon the presence or absence of either App or Prnp gene. Line 67 exhibit episodes of slow deliberate movement which last for a few days around weaning with a mild residual high stepping gait which persists into adult life. Other characteristics include plastic tail, 'praying behavior' and poor co-ordination that are also episodic. Presumptive mutant homozygotes die before weaning and exhibit a more severe phenotype with earlier onset. The most prominent characteristic associated with these presumptive homozygotes is a difficulty to right themselves when they roll on their back. Line 81 has a more complex phenotype however the most persistent characteristic is an intention tremor. PrP-null homozygotes are more reactive to changes in environmental conditions (e.g., hyperactive, aggressive) than null heterozygotes. Mapping studies are currently in progress to further define these two mutants.

This work was supported by the American Health Assistance Foundation

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