RANDOM MUTAGENESIS SCREEN FOR DOMINANT BEHAVIORAL MUTATIONS IN MICE

Large-scale mutagenesis and screening for altered phenotypes have been used effectively in many (lower) model organisms to identify mutation s in genes that control biological processes. In the mouse, the cost o f maintaining the large breeding colonies necessary to screen for rece ssive mutations makes it important to consider alternate approaches su ch as region-specific saturation mutagenesis or screening for mutation s with a dominant mode of inheritance. In this article, a pilot screen for (semi)dominant visible and behavioral mutations in the mouse indu ced by a potent chemical mutagen, N-ethyl-N-nitrosourea (ENU), is desc ribed. An efficient protocol for ENU mutagenesis and strain-specific d ifferences in the effect of mutagen on the sterility period and long-t erm survival are reported. In addition to a description of the screen for abnormal circadian wheel running activity that was used previously , the suitability of a high-throughput screen of mutagenized progeny i n the Porsolt swim test, used to test the efficacy of antidepressant a gents, and in the prepulse inhibition of the acoustic startle response , used to detect anomalies in sensorimotor gating, is tested, By demon strating strain specific differences and prescreening 100 G(1) progeny of mutagenized males, the feasibility of using these behavioral assay s for a large-scale screen is illustrated. In this review, details of a mutagenesis screen for behavioral abnormalities are described and is sues important in the initial characterization of novel ENU-induced mu tations are considered. (C) 1997 Academic Press.