Joseph Takahashi

Last updated
Joseph S. Takahashi
BornDecember 16, 1951 (1951-12-16) (age 72)
Tokyo, Japan
NationalityAmerican
Alma mater Swarthmore College
University of Oregon
Known forDiscovering CLOCK gene
Awards W. Alden Spencer Award (2001)
Scientific career
Fields Genetics
Neurobiology
Institutions UT Southwestern
Howard Hughes Medical Institute

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. [1] [2] Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. [3] [4] [5] Takahashi was elected to the National Academy of Sciences in 2003. [6]

Contents

Biography

Takahashi graduated from Richard Montgomery High School in Rockville, Maryland in 1970. [2] Takahashi attended Swarthmore College and graduated with a degree in biology in 1974. [6] 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. [6]

Takahashi was a postdoctoral fellow at the National Institute of Mental Health for two years under Martin Zatz before assuming a faculty position in Northwestern University's Department of Neurobiology and Physiology in 1983, where he held a 26-year tenure. [6] Takahashi joined the faculty at the University of Texas Southwestern Medical Center at Dallas in 2008 as their Loyd B. Sands Distinguished Chair in Neuroscience. [1] Takahashi also serves as a member of the Scientific Advisory Board of Hypnion Inc., a company focused on the development of novel therapeutics for central nervous system disorders affecting sleep and wake-alertness, as well as circadian rhythm abnormalities. [7] He also serves as a member of the editorial boards of Neuron , Physiological Genomics and Journal of Biological Rhythms . [8]

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, [9] which had been identified as the control center for circadian rhythms in mammals, played the same role in birds. [10] 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. [11]

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. [12]

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. [13] Using immunoprecipitation, Takahashi and Greenberg were able to show that light induced CREB phosphorylation occurs only during the subjective night. [14] Given that CREB has been shown to regulate c-fos transcription in PC12 pheochromocytoma cells, [15] Takahashi and Greenberg were able to conclude that phosphorylation of CREB in the SCN may play an important role in mammalian photic entrainment. [14]

After the in vitro research on the pineal gland culture system used to understand circadian oscillations, the limitations of the cell culture system were evident and Takahashi switched methods to begin using forward genetics and positional cloning—tools which required no advanced knowledge of the underlying mechanism—to understand the genetic and molecular bases of circadian rhythms. [6] [16] Using mutated mouse strains, Takahashi and his colleagues isolated strains with abnormal period length and discovered the clock gene in 1994. [17] They cloned the mammalian circadian clock gene in 1997. [6] [18]

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. [6] Since its discovery in 1988, the tau gene had been studied thoroughly, however, due to limited genomic resources in hamsters, the organism in which it was discovered, a problem existed preventing further study. Through the use of a genetically directed representational difference analysis (GDRDA), the fragments of DNA that differed between the mutant and wild type hamsters. With this information, Takahashi then used positional syntenic cloning to identify synteny with the human genome. This revealed that the gene is closely related to the gene doubletime (dbt) in Drosophila , and casein kinase 1 epsilon (CKIe) in humans, both of which interact with and regulate PER levels. [19]

Non-circadian phenotypes of the clock mutant mouse

Since identifying the clock mutant in 1994, [17] Takahashi has continued his research on this mutation and has applied it to studying clinical disorders, such as irregular sleep homeostasis and obesity. [20] [21]

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. [20] Additionally, because these mice lack the circadian system that regulates consolidated sleep at a certain time of day, sleep in clock mutants is spread out throughout the day in both light-dark cycles and in complete darkness. [20] This mutation results in less REM sleep and more time spent in earlier sleep phases. [20]

In 2005, he collaborated with Joseph Bass and reported the effects of mutations in the clock gene on the metabolism and physiology of mice. Their experiments compared weight gain in Clock mutant mice to that of control mice and showed that mutant mice were more likely to gain weight. Such a discovery influenced them to pursue exploration of the clock gene's role in appetite and energy. In Clock mutant mice, they reported depressed levels of orexin, a neuropeptide involved in regulation of eating. This result provides further evidence that the clock gene has a profound impact on metabolic processes in mice. [21]

It has since been discovered that metabolism itself plays a role in regulating the clock. [22] In 2009, Joseph Bass in collaboration with Takahashi's group discovered that nicotinamide phosphoribosyltransferase (NAMPT) mediated synthesis of metabolic coenzyme nicotinamide adenine dinucleotide (NAD+), which both oscillate on a daily cycle, may play an important role in regulating circadian activity. [22] 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. [22]

Continued mutagenesis studies

Using mutagenesis screens (forward genetics) found both the clock mutant mouse [18] and the tau mutant hamster. [6] Takahashi's lab has continued use of this method in order to lead to discoveries of the role of the circadian clock in vision, learning, memory, stress, and addiction, among other behavioral properties. [6] [2]

In 2007, Takahashi and his colleagues at Northwestern ran a forward mutagenesis screen in mice looking for variations in circadian oscillations and subsequently identified a mutant which they named overtime (Ovtm). [23] 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. [23] Takahashi and his colleagues proposed that FBXL3 is a target site for protein degradation on the CRY2 protein, which would explain relatively normal CRY2 protein levels. Negative feedback by other elements of the circadian clock could then lead to the roughly 26-hour free-running period observed in Ovtm mice. [23]

Awards and recognition

Notable papers

Related Research Articles

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximise the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

<span class="mw-page-title-main">Suprachiasmatic nucleus</span> Part of the brains hypothalamus

The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is the principal circadian pacemaker in mammals, responsible for generating circadian rhythms. Reception of light inputs from photosensitive retinal ganglion cells allow it to coordinate the subordinate cellular clocks of the body and entrain to the environment. The neuronal and hormonal activities it generates regulate many different body functions in an approximately 24-hour cycle.

<span class="mw-page-title-main">CREB</span> Class of proteins

CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.

<span class="mw-page-title-main">Melanopsin</span> Mammalian protein found in Homo sapiens

Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.

<span class="mw-page-title-main">FBXL3</span> Protein-coding gene in the species Homo sapiens

FBXL3 is a gene in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3). FBXL3 is a member of the F-box protein family, which constitutes one of the four subunits in the SCF ubiquitin ligase complex.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Human protein and coding gene

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

<span class="mw-page-title-main">Russell Foster</span>

Russell Grant Foster, CBE, FRS FMedSci is a British professor of circadian neuroscience, the Director of the Nuffield Laboratory of Ophthalmology and the Head of the Sleep and Circadian Neuroscience Institute (SCNi). He is also a Nicholas Kurti Senior Fellow at Brasenose College at the University of Oxford. Foster and his group are credited with key contributions to the discovery of the non-rod, non-cone, photosensitive retinal ganglion cells (pRGCs) in the mammalian retina which provide input to the circadian rhythm system. He has written and co-authored over a hundred scientific publications.

Michael Menaker, was an American chronobiology researcher, and was Commonwealth Professor of Biology at University of Virginia. His research focused on circadian rhythmicity of vertebrates, including contributing to an understanding of light input pathways on extra-retinal photoreceptors of non-mammalian vertebrates, discovering a mammalian mutation for circadian rhythmicity, and locating a circadian oscillator in the pineal gland of bird. He wrote almost 200 scientific publications.

<span class="mw-page-title-main">Casein kinase 1 isoform epsilon</span> Protein and coding gene in humans

Casein kinase I isoform epsilon or CK1ε, is an enzyme that is encoded by the CSNK1E gene in humans. It is the mammalian homolog of doubletime. CK1ε is a serine/threonine protein kinase and is very highly conserved; therefore, this kinase is very similar to other members of the casein kinase 1 family, of which there are seven mammalian isoforms. CK1ε is most similar to CK1δ in structure and function as the two enzymes maintain a high sequence similarity on their regulatory C-terminal and catalytic domains. This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms. CK1ε has also been implicated in modulating various human health issues such as cancer, neurodegenerative diseases, and diabetes.

Hitoshi Okamura is a Japanese scientist who specializes in chronobiology. He is currently a professor of Systems Biology at Kyoto University Graduate School of Pharmaceutical Sciences and the Research Director of the Japan Science Technology Institute, CREST. Okamura's research group cloned mammalian Period genes, visualized clock oscillation at the single cell level in the central clock of the SCN, and proposed a time-signal neuronal pathway to the adrenal gland. He received a Medal of Honor with Purple Ribbon in 2007 for his research and was awarded Aschoff's Ruler for his work on circadian rhythms in rodents. His lab recently revealed the effects of m6A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension.

The Society for Research on Biological Rhythms (SRBR) is an international chronobiological research society with three key goals:

  1. to promote the advancement and dissemination of basic and applied research in all aspects of biological rhythms.
  2. to enhance the education and training of students and researchers in the field.
  3. to foster interdisciplinary communication and an international exchange of ideas.

The food-entrainable oscillator (FEO) is a circadian clock that can be entrained by varying the time of food presentation. It was discovered when a rhythm was found in rat activity. This was called food anticipatory activity (FAA), and this is when the wheel-running activity of mice decreases after feeding, and then rapidly increases in the hours leading up to feeding. FAA appears to be present in non-mammals (pigeons/fish), but research heavily focuses on its presence in mammals. This rhythmic activity does not require the suprachiasmatic nucleus (SCN), the central circadian oscillator in mammals, implying the existence of an oscillator, the FEO, outside of the SCN, but the mechanism and location of the FEO is not yet known. There is ongoing research to investigate if the FEO is the only non-light entrainable oscillator in the body.

Martin R. Ralph is a circadian biologist who serves as a professor in the Psychology Department at the University of Toronto. His research primarily focuses on circadian rhythmicity in the fields of neuroscience, psychology, and endocrinology. His most notable work was has been on the suprachiasmatic nucleus, now recognized as the central circadian pacemaker in mammals, but has also investigated circadian rhythms in the context of time, memory, and light.

References

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  2. 1 2 3 "HHMI Scientist Biography - Joseph Takahashi". Howard Hughes Medical Institute. Retrieved 2009-04-24.
  3. ↑ "Gene Discovered in Mice that Regulates Biological Clock". Chicago Tribune. April 29, 1994.
  4. ↑ "Found in Mouse: The Gene of a Night Owl". The New York Times. April 29, 1994.
  5. ↑ Wade, Nicholas (May 16, 1997). "A Mouse Helps Explain What Makes Us Tick". The New York Times.
  6. 1 2 3 4 5 6 7 8 9 Marino, Melissa (April 13, 2004). "Biography of Joseph S. Takahashi". Proceedings of the National Academy of Sciences. 101 (15): 5336–5338. doi: 10.1073/pnas.0401895101 . PMC   399313 . PMID   15067124.
  7. ↑ "Hypnion, Inc. Raises $10.4 Million In Series A Private Equity Financing". Hypnion, Inc. Archived from the original on 10 September 2011. Retrieved 14 April 2011.
  8. ↑ "Joseph S. Takahashi Ph.D." Businessweek. Archived from the original on October 12, 2012. Retrieved 14 April 2011.
  9. ↑ Takahashi, J. S.; Hamm, H.; Menaker, M. (1980). "Circadian rhythms of melatonin release from individual superfused chicken pineal glands in vitro". Proc. Natl. Acad. Sci. 77 (4): 2319–2322. Bibcode:1980PNAS...77.2319T. doi: 10.1073/pnas.77.4.2319 . PMC   348706 . PMID   6929552.
  10. ↑ Takahashi, J. S.; Menaker, M. (1982). "Role of the suprachiasmatic nuclei in the circadian system of the house sparrow, Passer domesticus". Journal of Neuroscience. 2 (6): 718–726. doi:10.1523/JNEUROSCI.02-06-00815.1982. PMC   6564352 . PMID   7086486.
  11. ↑ Takahashi, J. S.; DeCoursey, P. J.; Bauman, L.; Menaker, M. (1984). "Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms". Nature. 308 (5955): 186–188. Bibcode:1984Natur.308..186T. doi:10.1038/308186a0. PMID   6700721. S2CID   4321911.
  12. ↑ Buhr, ED; Yoo, SH; Takahashi, JS (October 2010). "Temperature as a universal resetting cue for mammalian circadian oscillators". Science. 330 (6002): 379–85. Bibcode:2010Sci...330..379B. doi:10.1126/science.1195262. PMC   3625727 . PMID   20947768.
  13. ↑ Kornhauser, J.M.; Nelson, D.E.; Mayo, K.E.; Takahashi, J.S. (1990). "Photic and circadian regulation of c-fos gene expression in the hamster suprachiasmatic nucleus". Neuron. 5 (2): 127–134. doi:10.1016/0896-6273(90)90303-W. PMID   2116813. S2CID   43543601.
  14. 1 2 Ginty, D.D; Kornhauser, J.M.; Thompson, M.A.; Bading, H.; Mayo, K.E.; Takahashi, J.S.; Greenberg, M.E. (1993). "Regulation of CREB Phosphorylation in the Suprachiasmatic Nucleus by Light and a Circadian Clock". Science. 260 (5105): 238–241. Bibcode:1993Sci...260..238G. doi:10.1126/science.8097062. PMID   8097062.
  15. ↑ Sheng, M.; Thompson, M.A.; Greenberg, M.E. (1991). "CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases". Science. 252 (5011): 1427–1430. Bibcode:1991Sci...252.1427S. doi:10.1126/science.1646483. PMID   1646483.
  16. ↑ "PNAS Member Editor - Joseph Takahashi". Proceedings of the National Academy of Sciences. Archived from the original on 2021-04-28. Retrieved 2009-04-28.
  17. 1 2 Vitaterna, M.H.; King, D.P.; Chang, A.M.; Kornhauser, J.M.; Lowrey, P.L.; McDonald, J.D.; Dove, W.F.; Pinto, L.H.; Turek, F.W.; Takahashi, J.S. (1994). "Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior". Science. 264 (5159): 719–725. Bibcode:1994Sci...264..719H. doi:10.1126/science.8171325. PMC   3839659 . PMID   8171325.
  18. 1 2 King, David; Zhao, Yaliang; Sangoram, Ashvin; Wilsbacher, Lisa; Tanaka, Monuru; Antoch, Marina; Steeves, Thomas; Vitaterna; Kornhauser; Lowrey, Phillip; Turek, Fred; Takahashi, J.S. (1997). "Positional Cloning of the Mouse Circadian Clock Gene". Cell. 89 (4): 641–653. doi:10.1016/S0092-8674(00)80245-7. PMC   3815553 . PMID   9160755.
  19. ↑ "Joseph S. Takahashi, Ph.D." hhmi. Archived from the original on 7 October 2012. Retrieved 14 April 2011.
  20. 1 2 3 4 Naylor, Erik; Bergmann, Bernard M.; Krauski, Kristyn; Zee, Phyllis C.; Takahashi, Joseph D.; Vitaterna, Martha Hotz; Turek, Fred W. (November 2000). "The Circadian Clock Mutation Alters Sleep Homeostasis in the Mouse". The Journal of Neuroscience. 20 (21): 8138–8143. doi: 10.1523/JNEUROSCI.20-21-08138.2000 . PMC   6772726 . PMID   11050136.
  21. 1 2 Turek, F.W.; Joshu, C.; Kohsaka, A.; Lin, E; Ivanova, G.; McDearmon, E.; Laposky, A.; Losee-Olsen, S.; et al. (2005). "Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice". Science. 308 (5724): 1043–1045. Bibcode:2005Sci...308.1043T. doi:10.1126/science.1108750. PMC   3764501 . PMID   15845877.
  22. 1 2 3 Ramsey, Kathryn Moynihan; Jun Yoshino; Cynthia S. Brace; Dana Abrassart; Yumiko Kobayashi; Biliana Marcheva; Hee-Kyung Hong; Jason L. Chong; Ethan D. Buhr; Choogon Lee; Joseph S. Takahashi; Shin-ichiro Imai; Joseph Bass (May 2009). "Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis". Science. 324 (5927): 651–654. Bibcode:2009Sci...324..651R. doi:10.1126/science.1171641. PMC   2738420 . PMID   19299583.
  23. 1 2 3 Siepka, S.; Yoo, 2.; Park, J.; Song, W.; Kumar, V.; Hu, Y.; Lee, C.; Takahashi, J.S. (2007). "Circadian Mutant Overtime Reveals F-box Protein FBXL3 Regulation of Cryptochrome and Period Gene Expression". Cell. 129 (5): 1011–1023. doi:10.1016/j.cell.2007.04.030. PMC   3762874 . PMID   17462724.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  24. ↑ Marino, Melissa (2004-04-13). "Biography of Joseph S. Takahashi". Proceedings of the National Academy of Sciences. 101 (15): 5336–5338. doi: 10.1073/pnas.0401895101 . ISSN   0027-8424. PMC   399313 . PMID   15067124.
  25. ↑ Marino, Melissa (2004-04-13). "Biography of Joseph S. Takahashi". Proceedings of the National Academy of Sciences of the United States of America. 101 (15): 5336–5338. doi: 10.1073/pnas.0401895101 . ISSN   0027-8424. PMC   399313 . PMID   15067124.
  26. ↑ SRBR. "Joseph S. Takahashi Receives Gruber Neuroscience Prize | SRBR: Society for Research on Biological Rhythms" . Retrieved 2024-01-16.
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