PRODUCTION AND SCREENING OF MOUSE NEUROLOGICAL MUTATIONS

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The mouse has emerged as the premiere experimental mammal because of its power for analyzing known genes and for the variety of new heritable phenotypic variants available for study. Mouse genetics has made significant contributions to several complex areas of mammalian biology, but the central nervous system (CNS) is a challenge as its components are physically inter connected throughout life in complex networks and yet retain a great degree of plasticity. Recent progress in gene cloning, expression and gene targeting promise to further our knowledge, but genotype-based approaches alone are insufficient due to the CNS' interrelated and often redundant functions. The next step is to systematically collect a large number of mouse mutants for specific neurological disorders and mechanisms. Large-scale mutagenesis offers a progressive resource towards this end. We will establish a Neuroscience Mutagenesis Facility at The Jackson Laboratory to produce new mouse models for human neurological disease. We will generate new mutations using ENU in both genome-wide and specific genomic region screens, in both normal C57BL/6J mice and sensitized mutants. We will also implement new mutagenesis technologies that rely on treating embryonic stem cells with mutagens other than ENU, to make screens more efficient. Our broad phenotypic scope includes high-throughput screens in major focus areas of motor function, epilepsy, neural obesity, hearing, vision and learning, and we will work with collaborators or enable Visiting Investigators to develop high-throughput screens in areas such as ingestive behaviors, affective disorders, sensorimotor gating, substance abuse and anxiety. We will implement a distribution and sharing plan that provides the scientific community with widespread access to pathogen- free mice, sperm and embryos, and a database for experimental results as well as Internet access to all information generated and protocols used. We aim to place new neurological models per year into hands of the scientific community, and to preserve several hundred additional potential models for those who wish to pursue them. Our goal is to maximize the number of neurological mutants that become important research tools.