Joseph Takahashi

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003. He worked with Patricia DeCoursey at the University of South Carolina for a year after graduation and then applied to work with Michael Menaker at the University of Texas, Austin. Menaker ultimately moved to the University of Oregon where Takahashi received his neuroscience Ph.D. in 1981. He also serves as a member of the editorial boards of Neuron, Physiological Genomics and Journal of Biological Rhythms.

Research contributions

Studies of the SCN--the circadian pacemaker

In the early 1980s, Takahashi and Menaker studied the bird pineal gland culture system in vitro to understand circadian oscillations, and they demonstrated that the suprachiasmatic nucleus (SCN) of the hypothalamus, which had been identified as the control center for circadian rhythms in mammals, played the same role in birds. The authors also collaborated with DeCoursey and used hamsters to demonstrate that the photoreceptor system responsible for entrainment of circadian rhythms is different from that of the visual system.

In 2010 Takahashi, Buhr, and Yoo examined the potential of temperature fluctuations to entrain biological oscillators. The finding that the master circadian pacemaker, a robust oscillator which is typically only entrained by environmental light/dark cycles, was also capable of entraining to temperature fluctuations when isolated in vitro indicates that temperature resetting is a fundamental property of all mammalian clocks and likely works through a highly conserved mechanism in all mammalian cells. This also suggests that body temperature rhythms, as controlled by the SCN in homeothermic mammals, is a potential mechanism through which the master clock may synchronize circadian oscillators within tissues throughout the body.

Studies of circadian properties of mammalian clock genes

Takahashi's research has led to many developments in understanding how the circadian clock of mammals affects physiology and relationships with the environment. In 1993, Takahashi and Michael Greenberg studied the mechanisms of mammalian suprachiasmatic nuclei entrainment to environmental light cycles. They explored the relationship between phosphorylated cyclic adenosine monophosphate response element binding protein (CREB) and c-fos transcription, a protein previously indicated as a component of the photic entrainment pathway. Using immunoprecipitation, Takahashi and Greenberg were able to show that light induced CREB phosphorylation occurs only during the subjective night. Given that CREB has been shown to regulate c-fos transcription in PC12 pheochromocytoma cells, Takahashi and Greenberg were able to conclude that phosphorylation of CREB in the SCN may play an important role in mammalian photic entrainment. Using mutated mouse strains, Takahashi and his colleagues isolated strains with abnormal period length and discovered the clock gene in 1994. They cloned the mammalian circadian clock gene in 1997.

In 2000, Takahashi made what he calls one of his most significant contributions to the field, which was the cloning of the mutant tau gene identified in 1988 by Menaker and Martin Ralph.

Non-circadian phenotypes of the clock mutant mouse

Since identifying the clock mutant in 1994,

In 2000, he and his colleagues at Northwestern recognized that clock mutant mice slept 1 to 2 hours less per night than wild type mice. By measuring the oscillations of NAMPT and NAD+ levels in the livers of both wild-type and mutant mice they determined that oscillations in NAMPT regulated NAD+ which in turn regulated the deacetylase SIRT1. Using positional cloning, genetic complementation, and in-situ hybridization Takahashi and colleagues discovered that Ovtm was a point mutation that caused a loss of function in FBXL3 – an F-box protein – and was expressed throughout the brain and in the SCN. Assaying expression of known circadian clock genes in the Ovtm mutants, they observed a marked decrease in PER1 and PER2 protein and mRNA levels in the brain and a significant decrease in cry2 mRNA levels only.

Notable papers

This paper discusses the circadian cycle of Clock-Bmal activating the transcription of Cry1, 2, and Per proteins which represses Clock-Bmal transcription creating daily cycling of transcription and channel activation. Specifically, Takahashi looks at NAD+ and NAMPT levels in the liver.