Proceedings of the National Academy of Sciences of the United States of America

About the PNAS Member Editor
Name Takahashi, Joseph S.
Location The University of Texas Southwestern Medical Center at Dallas
Primary Field Cellular and Molecular Neuroscience
Secondary Field Systems Neuroscience
 Election Citation
Takahashi pioneered the use of forward genetics and positional cloning in the mouse as a tool for the discovery of the genes underlying neurobiology and behavior. His discovery of the mouse and human Clock genes led to a description of a conserved circadian clock mechanism in animals. He presently uses genetics to approach complex behaviors such as learning and memory.
 Research Interests
My colleagues and I study the mechanism of circadian rhythms in vertebrates. Circadian rhythms are of interest because they represent an evolutionarily conserved adaptation to the environment that can be traced back to the earliest life forms and because in animals circadian behavior can be analyzed as an integrated system - beginning with genes leading ultimately to behavioral outputs. Initially, our work focused on the localization of circadian oscillators in nervous systems of birds and mammals. Then, led to a more mechanistic study of how these oscillators functioned by isolating them in vitro. The key breakthroughs in the field however came from genetics and the identification of 'clock genes' first in Drosophila and Neurospora. In the last decade, we have used the mouse as a tool for the discovery of genes that control circadian behavior. In work with William F. Dove, my colleagues and I used a phenotype-driven mutagenesis strategy to isolate the first circadian rhythm mutant in the mouse (named Clock). This led to the identification of the Clock gene by a combination of transgenic "rescue" and positional cloning. These experiments revealed that Clock encoded a novel member of the basic-helix-loop-helix - PAS family of transcription factors. In subsequent work, we found that CLOCK and its partner BMAL1 act as the positive elements of a transcriptional feedback loop that generates circadian oscillations. The primary targets of CLOCK are the Period and Cryptochrome genes which comprise the negative feedback elements of the oscillator. Recently, we have continued to use genetics to dissect circadian behavior and have extended this approach to other types of complex behaviors.

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