Hitoshi Okamura

Hitoshi Okamura
Born (1952-12-02)December 2, 1952
Residence Japan
Nationality Japanese
Fields Chronobiology, Physiology
Website
Okamura Lab

Hitoshi Okamura (born December 2, 1952)[1] MD/PhD, 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.[2] 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.[3]

Education

Hitoshi Okamura received his undergraduate, medical, and doctorate in science degrees from the Kyoto Prefectural University of Medicine. After training as a pediatrician at the Children's Medical Center of the Okayama National Hospital (1979-1981), he worked on neuroanatomy at the Kyoto Prefectural University of Medicine (1981-1995). He was then a Professor of Brain Sciences at the Kobe University School of Medicine from 1995-2008.[4] Since 2007, he has worked as a Professor of Systems Biology at the Kyoto University Graduate School of Pharmaceutical Sciences.[5] Since 2014, he has worked as the Research Director of the Japan Science Technology Institute, CREST. His work has focused on understanding mammalian circadian rhythms.

Awards and honors

Scientific contributions

Suprachiasmatic Nucleus research

Okamura began his study of circadian rhythms in 1982 with the peptide work in the suprachiasmatic nucleus (SCN) using the technique of histochemistry in Yasuhiko Ibata's laboratory in the Kyoto Prefectural University of Medicine. He established quantitative histochemistry of the suprachiasmatic nucleus (SCN) in the 1980s, and together with Shin-Ichi Inouye, established in vitro slice cultures of the SCN in the early 1990s.[6]

Discovery of Mammalian Period Genes

In 1997, Hajime Tei, Yoshiyuki Sakaki, and Hitoshi Okamura discovered the mammalian period gene PER1 in mice and humans. They also discovered PER2, PER3, and the mammalian homolog of the Drosophila gene timeless.[7] They found that Per1 is light-inducible and can phase shift the circadian clock by light.[8] Okamura worked with Jay Dunlap, a chronobiologist specializing in circadian rhythms in Neurospora, to show that mammalian clocks are similar to neurospora clocks in their use of induction to phase shift. This is in contrast to the drosophila clock, which phase shift via protein degradation rather than induction.[9]

Protein Level Regulation of Mammalian Per

Okamura's team discovered that mammalian PER proteins made in the cytoplasm translocate into the nucleus of the cell and form a complex composed of CRY1, CRY2, PER1, PER2, PER3, and TIM.[10] This negative complex suppresses the transcription of mRNA activated by CLOCK and BMAL1.[11] Okamura has also done research on mPER1 and mPER2 degradation. They found that PER and CRY form a dimer that inhibits PER degradation and that the inhibition of PER degradation suppresses Per1 and Per2 transcription.[10] This negative feedback loop appears to be found in all clocks.[12]

Core clock loop of clock genes is universal among mammalian cells

Okamura became interested in the possible differences of autonomously rhythmic clock genes in fibroblast cell lines and those in the SCN. His team discovered that in mice, both types of cells showed temporal expression of profiles of all known clock genes,[13] the phases of various mRNA rhythms, the delay between maximum mRNA levels and appearance of nuclear PER1 and PER2 protein, the inability to produce circadian oscillations in the absence of functional Cry genes, and the control of period length by CRY proteins.

Total Loss of Oscillation in mCry1/mCry2-double knockout mice

Okamura collaborated with Gijsbertus T.J. van der Horst and found that both peripheral and central clocks are stopped in Cry deficient mice.[11] Okamura also collaborated with Shin-Ichi Inouye to find that behavioral circadian rhythmicity was recovered when the SCN from wild-type mice was transplanted into Cry deficient mice. This suggests that the suprachiasmatic nucleus (SCN) synchronizes and generates behavioral rhythms.[14]

Restoration of Circadian Rhythms Using Mammalian Per

Okamura collaborated with Amita Sehgal to determine if the mPer1 and mPer2 genes were able to generate circadian oscillations.[5] They transplanted Per1 and Per2 genes from mice into arrhythmic per0 mutants of Drosophila and found that transplantation restored circadian rhythms.[15]

SCN as the Central Clock

Okamura's team also analyzed the SCN at the cellular level. They succeeded in monitoring the rhythmic transcription of genes at the single cell level in real-time. This work was achieved by combining the SCN slice-culture technique, transgenic mice carrying the luciferase gene driven by the Per1 promoter (Per1-luc), and the cryogenic high resolution CCD camera. They have demonstrated that a stable ensemble SCN rhythm is orchestrated within an assembly of cellular clocks that are differentially phased and that sit in a distinct topographic order in the SCN. Tetrodotoxin, which blocks action potentials, not only desynchronizes the cell population, but also suppresses the level of clock gene expression, demonstrating that neuronal networks play a dominant role in oscillation of rhythms in the SCN. Using the same Per-luc mice with the optical fiber inserted to the brain, Okamura's team succeeded in monitoring the rhythmic gene expression of the clock gene in real-time in freely moving mice, demonstrating that the Per gene is activated in the daytime and rests in the nighttime in the SCN. Okamura discovered that flashing NMDA, which is analogous to light stimuli, instantly altered the phase of the core clock oscillation of a slice of SCN.[16] This proved that there is rhythmic transcription of genes at the single cell level. It has been shown that the SCN regulates peripheral clocks by regulating melatonin in the sympathetic nervous system.[17] Okamura's team also demonstrated that the light can activate genes and corticosterone secretion in the adrenal gland through the SCN-sympathetic nerve routes. So, the sympathetic nerve conveys the time signal of the core central clock (SCN) to peripheral organs, and the adrenal gland is the key organ in transforming circadian signals from nerve signals to the endocrine signals.[14]

Cell Clock and Cell Cycle

Okamura's team has also looked into the relationship between the circadian clock and the cell cycle. They performed DNA arrays and Northern blots to characterize the molecular differences in M-phase entry and found that cyclin B1 and cdc2 were positively correlated. They also found that wee1, the gene for a kinase that inhibits mitosis by inactivating CDC2/cyclin B, was negatively correlated to M-phase.[18] Their research showed that mouse hepatocyte proliferation is under circadian control.[19]

Current research pursuits

In more recent years, Okamura and his team extended their molecular clock work to posttranscriptional, intercellular, and systemic levels.[20] They found the mRNA methylation alters the speed of circadian rhythms [21] and heterogeneity of G protein signaling is necessary for time-keeping in the SCN.[22] Moreover, they found the dysregulated clock induces salt-sensitive hypertension through the inappropriate secretion of aldosterone.[23] Another discovery was that clock regulation of gap junction protein in the urinary bladder was a cause of abnormal urination.[24] Very recently, they found that vasopressin signaling in the SCN is crucial for jet lag.[25][26]

Now, Okamura continues investigations of biological clocks, fascinated with the integrational characteristics of "time" in a vertical arrangement, providing a bridge between single genes and the living organism as a whole.

Comprehensive timeline [1][5]

Name Year
Born 1952
Becomes a professor in the Department of Anatomy II/Lab at Kobe University 1995
Discovery of mammalian Per1, Per2, Per3, Timeless 1997, 1998
Found that mPer is light-inducible 1998
Discovery that clock proteins form complexes and prevent degradation 2000, 2002, 2005
Work on fibroblasts and the universality of the core clock loop among mammalian cells 2001
Loss of oscillations in Cry deficient mice 2001
SCN transplantation restored circadian rhythms 2003
Core clock regulates cell cycle 2003
Light activates the adrenal gland via SCN-sympathetic nerves 2005
Received Medal of Honor with Purple Ribbon 2007
Became Professor of Systems Biology at Kyoto University/Pharmaceutical Sciences 2007
Received Aschoff's Ruler 2009
The role of dysregulated clocks in salt-sensitive hypertension 2010
Circadian G protein signaling RGS16 in the SCN 2011
mRNA methylation in regulation of circadian period length 2013
Vasopressin is critical for jet lag 2013
Became Research Director of the Japan Science Technology Institute, CREST 2014

References

  1. 1 2 "Kyoto University Activity Database on Education and Research".
  2. ↑ "Prize Winners of Aschoff's Ruler". EBRS.
  3. ↑ Fustin, Jean-Michael; Doi, Masao; Yamaguchi, Yoshiaka; Nishimura, Shinichi; Yoshia, Minoru; Isagawa, Takayuki; Morioka, Masaki; Kayeka, Hideaki; Manabe, Ichiro; Okamura, Hitoshi (November 7, 2013). "RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock". Cell. 155 (4): 793–806. doi:10.1016/j.cell.2013.10.026. PMID 24209618.
  4. ↑ "Prof Hitoshi Okamura". ISH 2012.
  5. 1 2 3 "Okamura Laboratory". Kyoto University Graduate School of Pharmaceutical Sciences, Department of Systems Biology.
  6. ↑ Tanaka, Masani; Ichitani, Yukio; Hitoshi, Okamura; Tanaka, Yoshifumi; Ibata, Yasuhiko (14 December 1992). "The direct retinal projection to VIP neuronal elements in the rat SCN". Brain Research Bulletin. 31: 637–640. doi:10.1016/0361-9230(93)90134-w.
  7. ↑ Reppert, Steven M; Weaver, David R (2001). "Molecular Analysis of Mammalian Circadian Rhythms". Annual Review of Physiology. 63 (1): 647–676. doi:10.1146/annurev.physiol.63.1.647. ISSN 0066-4278.
  8. ↑ Albrecht, Urs; Zheng, Binhai; Larkin, David; Sun, Zhong; Lee, Cheng (April 2001). "mPer1 and mPer2 Are Essential for Normal Resetting of the Circadian Clock". Journal of Biological Rhythms. 16 (2): 100–104. doi:10.1177/074873001129001791. PMID 11302552.
  9. ↑ Liu, Yi (June 2003). "Molecular Mechanisms of Entrainment in the Neurospora Circadian Clock". Journal of Biological Rhythms. 18 (3): 195–205. doi:10.1177/0748730403018003002.
  10. 1 2 Preitner, Nicolas; Damiola, Francesca; Lopez-Molina, Luis; Zakany, Joszef; Duboule, Denis; Albrecht, Urs; Schibler, Ueli (26 July 2002). "The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator". Cell. 110 (2): 251–260. doi:10.1016/S0092-8674(02)00825-5. PMID 12150932.
  11. 1 2 Reppert, Steven M.; Weaver, David R. (2002). "Coordination of circadian timing in mammals". Nature. 418 (6901): 935–941. doi:10.1038/nature00965. ISSN 0028-0836. PMID 12198538.
  12. ↑ Balsalobre, Aurélio (24 January 2014). "Clock genes in mammalian peripheral tissues". Cell and Tissue Research. 309 (1): 193–199. doi:10.1007/s00441-002-0585-0.
  13. ↑ Hastings, Michael; Reddy, Akhilesh; Maywood, Elizabeth (August 2003). "A clockwork web: circadian timing in brain and periphery, in health and disease". Nature Reviews Neuroscience. 4: 649–661. doi:10.1038/nrn1177.
  14. 1 2 Dibner, Charna; Schibler, Ueli; Albrecht, Urs (2010). "The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks". Annual Review of Physiology. 72 (1): 517–549. doi:10.1146/annurev-physiol-021909-135821. ISSN 0066-4278. PMID 20148687.
  15. ↑ Hendricks, Joan C. (2003). "Invited Review: Sleeping flies don't lie: the use of Drosophila melanogaster to study sleep and circadian rhythms". Journal of Applied Physiology. 94 (4): 1660–1672. doi:10.1152/japplphysiol.00904.2002. ISSN 8750-7587.
  16. ↑ Colwell, Christopher (20 December 2001). "NMDA-evoked calcium transients and currents in the suprachiasmatic nucleus: gating by the circadian system". European Journal of Neuroscience. 13 (7): 1420–1428. doi:10.1046/j.0953-816x.2001.01517.x.
  17. ↑ Bartness, Timothy; Demas, Gregory; Song, C. Kay (2002). "Seasonal Changes in Adiposity: the Roles of the Photoperiod, Melatonin and Other Hormones, and Sympathetic Nervous System". Experimental Biology and Medicine. 227.
  18. ↑ Mitra, Jayashree; Schultz, Richard (1 September 1996). "Regulation of the acquisition of meiotic competence in the mouse: changes in the subcellular localization of cdc2, cyclin B1, cdc25C and wee1, and in the concentration of these proteins and their transcripts". Journal of Cell Science: 2407–2415.
  19. ↑ Fausto, Nelson; Campbell, Jean S.; Riehle, Kimberly J. (2006). "Liver regeneration". Hepatology. 43 (S1): S45–S53. doi:10.1002/hep.20969. ISSN 0270-9139. PMID 16447274.
  20. ↑ "Raku-Yu" (PDF). Kyoto University Newsletter (Autumn 2014). 2014. Retrieved 2015-04-23.
  21. ↑ Archer, S. N.; Laing, E. E.; Moller-Levet, C. S.; van der Veen, D. R.; Bucca, G.; Lazar, A. S.; Santhi, N.; Slak, A.; Kabiljo, R.; von Schantz, M.; Smith, C. P.; Dijk, D.-J. (2014). "PNAS Plus: From the Cover: Mistimed sleep disrupts circadian regulation of the human transcriptome". Proceedings of the National Academy of Sciences. 111 (6): E682–E691. doi:10.1073/pnas.1316335111. ISSN 0027-8424.
  22. ↑ Doi, Masao; Ishida, Atsushi; Miyake, Akiko; Sato, Miho; Komatsu, Rie; Yamazaki, Fumiyoshi; Kimura, Ikuo; Tsuchiya, Soken; Kori, Hiroshi; Seo, Kazuyuki; Yamaguchi, Yoshiaki; Matsuo, Masahiro; Fustin, Jean-Michel; Tanaka, Rina; Santo, Yasuko; Yamada, Hiroyuki; Takahashi, Yukari; Araki, Michihiro; Nakao, Kazuki; Aizawa, Shinichi; Kobayashi, Masaki; Obrietan, Karl; Tsujimoto, Gozoh; Okamura, Hitoshi (2011). "Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus". Nature Communications. 2: 327. doi:10.1038/ncomms1316. ISSN 2041-1723.
  23. ↑ Nikolaeva, S.; Pradervand, S.; Centeno, G.; Zavadova, V.; Tokonami, N.; Maillard, M.; Bonny, O.; Firsov, D. (2012). "The Circadian Clock Modulates Renal Sodium Handling". Journal of the American Society of Nephrology. 23 (6): 1019–1026. doi:10.1681/ASN.2011080842. ISSN 1046-6673.
  24. ↑ Timóteo, M. Alexandrina; Carneiro, Inês; Silva, Isabel; Noronha-Matos, José Bernardo; Ferreirinha, Fátima; Silva-Ramos, Miguel; Correia-de-Sá, Paulo (2014). "ATP released via pannexin-1 hemichannels mediates bladder overactivity triggered by urothelial P2Y6 receptors". Biochemical Pharmacology. 87 (2): 371–379. doi:10.1016/j.bcp.2013.11.007. ISSN 0006-2952.
  25. ↑ Sporns, Olaf; Ananthasubramaniam, Bharath; Herzog, Erik D.; Herzel, Hanspeter (2014). "Timing of Neuropeptide Coupling Determines Synchrony and Entrainment in the Mammalian Circadian Clock". PLoS Computational Biology. 10 (4): e1003565. doi:10.1371/journal.pcbi.1003565. ISSN 1553-7358.
  26. ↑ Yamaguchi, Yoshiaki; Suzuki, Toru; Mizoro, Yasutaka; Kori, Hiroshi (October 2013). "Mice Genetically Deficient in Vasopressin V1a and V1b Receptors Are Resistant to Jet Lag". Science. 4: 85–90. doi:10.1126/science.1238599.
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