Joseph S. Takahashi, PhD

Walter and Mary E. Glass Professor in the Life Sciences
Department of Neurobiology and Physiology
Weinberg College of Arts and Sciences

Research Interests:
The long-term objectives of Dr. Joseph Takahashi’s research are to understand the cellular and molecular mechanisms that regulate circadian rhythms. They have used a "forward genetics" approach (from phenotype to gene) to study the mechanism of circadian rhythms in mammals using the mouse as a model organism. Using an ENU mutagenesis screen for circadian rhythm variants, his lab isolated the first circadian mutation in mice which is named Clock. The Clock mutation is semidominant and lengthens circadian period by 1 hr in heterozygotes and by 4 hr in homozygotes. Importantly Clock homozygotes lose persistent circadian rhythms in constant darkness. The Clock mutation maps to the midportion of chromosome 5 in the mouse. In 1997, they identified the gene encoding the Clock mutation by the method of positional cloning and by functional rescue of the Clock mutant phenotype by transgenic expression in mice of large-insert genomic BAC clones. Clock encodes a novel member of the basic-helix-loop-helix (bHLH)-PAS domain family of transcription factors. In the ENU-induced Clock mutant allele, Dr. Takahashi’s lab identified a single A to T nucleotide transversion in a splice donor site which causes exon skipping and the deletion of 51 amino acids in the C-terminal region of the CLOCK protein.

Recently, They have found that the CLOCK protein dimerizes with another bHLH-PAS protein known as BMAL1 (aka, MOP3, JAP3). The CLOCK-BMAL1 heterodimer binds to and transactivates through an E-box motif (-CACGTG-) found in the period gene promoters of both Drosophila and mice. The Drosophila orthologs of Clock and BMAL1 have also been identified and play the same role. Thus, the CLOCK protein and its partner are positive regulators of period (and timeless) gene transcription. In Drosophila Dr. Takahashi’s lab has found that the PERIOD and TIMELESS proteins subsequently inhibit their own transcription via the CLOCK-BMAL1 complex. These four genes define a basic framework for a transciptional autoregulatory loop that appears to compose the circadian oscillator mechanism in animals. The delineation of this circadian gene pathway should eventually lead to an understanding of how circadian clocks function, how they are regulated by environmental inputs, and how clocks regulate their various outputs.