International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

E4. Forward Genetics in the Mouse: Gene Discovery and Functional Analysis of Circadian and Brain Pathways

Joseph S. Takahashi
Howard Hughes Medical Institute, Dept Neurobiology & Physiology, Northwestern University, Evanston, IL 60208

As the human genome project approaches completion and the sequence of 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. In the context of the brain and behavior, genome-wide approaches are necessary to identify novel and previously unknown pathways underlying these complex phenotypes. We have used circadian rhythms as a model for genetic dissection of behavior in the mouse. During the past four years, significant progress has been made in identifying the molecular components of the mammalian circadian clock system. ENU mutagenesis provided a crucial molecular entry point for the analysis of the circadian pathway. An autoregulatory transcriptional feedback loop similar to that described in Drosophila appears to form the core circadian rhythm generating mechanism in mammals. Two basic helix-loop-helix (bHLH) PAS (PER-ARNT-SIM) transcription factors, CLOCK and BMAL1, form the positive elements of the system and drive transcription of three Period and two Cryptochrome genes. The protein products of these genes are components of a negative feedback complex that inhibits CLOCK and BMAL1 to close the circadian loop. In recent work, we have cloned the hamster tau mutation using a positional syntenic approach and found that it is encoded by Casein kinase I epsilon, a homologue of the Drosophila circadian gene, double-time, defining yet another level (post-translational) of conservation of the circadian mechanism. Such forward genetic approaches should have broad application in the field of neuroscience in the future.

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