Mouse Mutagenesis: Phenotype-Driven Neuroscience Screens

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The overall objectives of this proposal are to create a Center that will focus on large-scale ENU mutagenesis screens in five phenotypic domains relevant to the nervous system and behavior. We have carefully chosen to focus upon five phenotypic screens: 1) circadian rhythms, 2) fear conditioning, 3) vision, 4) neuroendocrine hormones, and 5) response to psychostimulants. In order for us to include a screen, we have established the following set of criteria: * the biological context of the phenotype must be mature and of significance to neuroscience; * the characterization of mutants in the phenotypic class is well established; * the phenotypic screen must be amenable to automation and scaling; * the initial screen must be capable of a throughput of at least 10,000 mice per year; * the investigators involved in the screens and their follow up must be leading experts in the field. Our aims are: 1. To conduct a large-scale, genome-wide, phenotype-driven ENU mutagenesis screen for recessive mutations that targets five domains influencing the nervous system and behavior. 2. To screen, isolate and characterize mutations that alter the circadian phenotype of mice. 3. To screen, isolate and characterize mutations that alter context- dependent and cued fear conditioning in mice. 4. To screen, isolate and characterize mutations that alter vision using three different methods: electroretinogram (ERG), visually evoked potentials (VEP) and fundus photography. 5. To screen, isolate and characterize mutations that alter the hypothalmic-adrenal (HPA) axis and the hypothalamic-thyroid (HPT) axis. 6. To screen, isolate and characterize mutations that alter the response of mice to psychostimulant treatment. 7. To act as a national resource for mouse mutants by providing rapid access to phenotypic screening analyses "online" so that mice are accessible to the greater scientific community. As the human genome project progresses and the sequences of more human and mouse genes are determined, the function of a large number of genes will not be predictable by sequence and expression alone. Phenotype-driven mutagenesis screens provide an important approach to understand the function of these genes.