Updated on 2021/05/19

写真a

 
HATORI Megumi
 
Organization
Institute of Transformative Bio-Molecules Designated associate professor
Title
Designated associate professor

Degree 1

  1. 博士(理学) ( 2007.3   東京大学 ) 

Research Areas 1

  1. Life Science / Animal physiological chemistry, physiology and behavioral biology

Current Research Project and SDGs 1

  1. 概日時計の環境応答

 

Papers 25

  1. Isoform-selective regulation of mammalian cryptochromes Reviewed

    Miller, S., Son, Y.L., Aikawa, Y., Makino, E., Nagai, Y., Srivastava, A., Oshima, T., Sugiyama, A., Hara, A., Abe, K., Hirata, K., Oishi, S., Hagihara, S., Sato, A., Tama, F., Itami, K., Kay, S.A., Hatori, M., Hirota, T.

    Nature Chemical Biology   Vol. 16 ( 6 ) page: 676 - 685   2020.6

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    DOI: 10.1038/s41589-020-0505-1

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  2. Synaptic Specializations of Melanopsin-Retinal Ganglion Cells in Multiple Brain Regions Revealed by Genetic Label for Light and Electron Microscopy Reviewed

    Kim, K.-Y., Rios, L.C., Le, H., Perez, A.J., Phan, S., Bushong, E.A., Deerinck, T.J., Liu, Y.H., Ellisman, M.A., Lev-Ram, V., Ju, S., Panda, S.A., Yoon, S., Hirayama, M., Mure, L.S., Hatori, M., Ellisman, M.H., Panda, S.

    Cell Reports   Vol. 29 ( 3 ) page: 628 - 644.e6   2019.10

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    DOI: 10.1016/j.celrep.2019.09.006

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  3. Sustained Melanopsin Photoresponse Is Supported by Specific Roles of β-Arrestin 1 and 2 in Deactivation and Regeneration of Photopigment Reviewed

    Mure, L.S., Hatori, M., Ruda, K., Benegiamo, G., Demas, J., Panda, S.

    Cell Reports   Vol. 25 ( 9 ) page: 2497 - 2509.e4   2018.11

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    DOI: 10.1016/j.celrep.2018.11.008

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  4. Global rise of potential health hazards caused by blue light-induced circadian disruption in modern aging societies Reviewed

    Hatori, M., Gronfier, C., Van Gelder, R.N., Bernstein, P.S., Carreras, J., Panda, S., Marks, F., Sliney, D., Hunt, C.E., Hirota, T., Furukawa, T., Tsubota, K.

    npj Aging and Mechanisms of Disease   Vol. 3 ( 1 ) page: 9   2017.6

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    DOI: 10.1038/s41514-017-0010-2

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  5. Violet Light Exposure Can Be a Preventive Strategy Against Myopia Progression Reviewed

    Torii, H., Kurihara, T., Seko, Y., Negishi, K., Ohnuma, K., Inaba, T., Kawashima, M., Jiang, X., Kondo, S., Miyauchi, M., Miwa, Y., Katada, Y., Mori, K., Kato, K., Tsubota, K., Goto, H., Oda, M., Hatori, M., Tsubota, K.

    EBioMedicine   Vol. 15   page: 210 - 219   2017.2

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    Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER SCIENCE BV  

    Prevalence of myopia is increasing worldwide. Outdoor activity is one of the most important environmental factors for myopia control. Here we show that violet light (VL, 360-400 nm wavelength) suppresses myopia progression. First, we confirmed that VL suppressed the axial length (AL) elongation in the chick myopia model. Expression microarray analyses revealed that myopia suppressive gene EGR1 was upregulated by VL exposure. VL exposure induced significantly higher upregulation of EGR1 in chick chorioretinal tissues than blue light under the same conditions. Next, we conducted clinical research retrospectively to compare the AL elongation among myopic children who wore eyeglasses (VL blocked) and two types of contact lenses (partially VL blocked and VL transmitting). The data showed the VL transmitting contact lenses suppressed myopia progression most. These results suggest that VL is one of the important outdoor environmental factors for myopia control. Since VL is apt to be excluded from our modern society due to the excessive UV protection, VL exposure can be a preventive strategy against myopia progression. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

    DOI: 10.1016/j.ebiom.2016.12.007

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  6. Crosstalk of the circadian clock, light response, feeding and aging. Reviewed

    Tsuyama J, Hatori M

    Nihon rinsho. Japanese journal of clinical medicine   Vol. 74 ( 9 ) page: 1474 - 1478   2016.9

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  7. Melanopsin-Encoded Response Properties of Intrinsically Photosensitive Retinal Ganglion Cells Reviewed

    Mure, L.S., Hatori, M., Zhu, Q., Demas, J., Kim, I.M., Nayak, S.K., Panda, S.

    Neuron   Vol. 90 ( 5 ) page: 1016 - 27   2016.6

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    Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    Melanopsin photopigment expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs) plays a crucial role in the adaptation of mammals to their ambient light environment through both image-forming and non-image-forming visual responses. The ipRGCs are structurally and functionally distinct from classical rod/cone photoreceptors and have unique properties, including single-photon response, long response latency, photon integration over time, and slow deactivation. We discovered that amino acid sequence features of melanopsin protein contribute to the functional properties of the ipRGCs. Phosphorylation of a cluster of Ser/Thr residues in the C-terminal cytoplasmic region of melanopsin contributes to deactivation, which in turn determines response latency and threshold sensitivity of the ipRGCs. The poorly conserved region distal to the phosphorylation cluster inhibits phosphorylation's functional role, thereby constituting a unique delayed deactivation mechanism. Concerted action of both regions sustains responses to dim light, allows for the integration of light over time, and results in precise signal duration.

    DOI: 10.1016/j.neuron.2016.04.016

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  8. X-Ray Microscopy as an Approach to Increasing Accuracy and Efficiency of Serial Block-Face Imaging for Correlated Light and Electron Microscopy of Biological Specimens Reviewed

    Bushong, E.A., Johnson, D.D., Kim, K.-Y., Terada, M., Hatori, M., Peltier, S.T., Panda, S., Merkle, A., Ellisman, M.H.

    Microscopy and Microanalysis   Vol. 21 ( 1 ) page: 231 - 8   2015.2

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    Publishing type:Research paper (scientific journal)   Publisher:CAMBRIDGE UNIV PRESS  

    The recently developed three-dimensional electron microscopic (EM) method of serial block-face scanning electron microscopy (SBEM) has rapidly established itself as a powerful imaging approach. Volume EM imaging with this scanning electron microscopy (SEM) method requires intense staining of biological specimens with heavy metals to allow sufficient back-scatter electron signal and also to render specimens sufficiently conductive to control charging artifacts. These more extreme heavy metal staining protocols render specimens light opaque and make it much more difficult to track and identify regions of interest (ROIs) for the SBEM imaging process than for a typical thin section transmission electron microscopy correlative light and electron microscopy study. We present a strategy employing X-ray microscopy (XRM) both for tracking ROIs and for increasing the efficiency of the workflow used for typical projects undertaken with SBEM. XRM was found to reveal an impressive level of detail in tissue heavily stained for SBEM imaging, allowing for the identification of tissue landmarks that can be subsequently used to guide data collection in the SEM. Furthermore, specific labeling of individual cells using diaminobenzidine is detectable in XRM volumes. We demonstrate that tungsten carbide particles or upconverting nanophosphor particles can be used as fiducial markers to further increase the precision and efficiency of SBEM imaging.

    DOI: 10.1017/S1431927614013579

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  9. Response of peripheral rhythms to the timing of food intake Reviewed

    Hatori, M., Panda, S.

    Methods in Enzymology   Vol. 552   page: 145 - 61   2015

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    Publishing type:Research paper (scientific journal)   Publisher:Methods in Enzymology  

    Metabolism and physiology in animals show diurnal rhythm to adapt to the daily cycles of activity-rest and the associated rhythm in feeding and fasting. Accordingly, gene expression, protein activities, and numerous metabolites show daily rhythm in abundance. The significance of these rhythms in promoting healthy lifespan and preventing disease has recently come to light. Mice with genetic disruption of circadian rhythm, mice, and humans under shift-work paradigm, and mice fed high-fat diet ad libitum exhibit chronic disruption of feeding-fasting rhythm and dampened daily rhythms in physiology, metabolism, and gene expression. These dampened rhythms are associated with metabolic diseases. Conversely, time-restricted feeding, in which mice are fed for certain number of hours every day, restores rhythms and can prevent obesity and metabolic diseases even when mice are fed high-fat diet. These observations seek mechanistic explanations, which will require careful experiments in which feeding duration, genotype, nutrient, and feeding time relative to light: dark cycle will be manipulated and molecular changes in peripheral organs and a few brain regions will be assessed. This chapter will primarily focus on the use of mouse as an experimental animal and the experimental setup so that the molecular readouts can be better interpreted.

    DOI: 10.1016/bs.mie.2014.10.027

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  10. Lhx1 maintains synchrony among circadian oscillator neurons of the SCN Reviewed

    Hatori, M., Gill, S., Mure, L.S., Goulding, M., O'leary, D.D.M., Panda, S.

    eLife   Vol. 3 ( July2014 ) page: e03357   2014.7

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    Publishing type:Research paper (scientific journal)   Publisher:ELIFE SCIENCES PUBLICATIONS LTD  

    The robustness and limited plasticity of the master circadian clock in the suprachiasmatic nucleus (SCN) is attributed to strong intercellular communication among its constituent neurons. However, factors that specify this characteristic feature of the SCN are unknown. Here we identified Lhx1 as a regulator of SCN coupling. A phase-shifting light pulse causes acute reduction in Lhx1 expression and of its target genes that participate in SCN coupling. Mice lacking Lhx1 in the SCN have intact circadian oscillators, but reduced levels of coupling factors. Consequently, the mice rapidly phase shift under a jetlag paradigm and their behavior rhythms gradually deteriorate under constant conditions. Ex vivo recordings of the SCN from these mice showed rapid desynchronization of unit oscillators. Therefore, by regulating the expression of genes mediating intercellular communication, Lhx1 imparts synchrony to SCN neurons and ensures consolidated rhythms of activity and rest that are resistant to photic noise.

    DOI: 10.7554/eLife.03357

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  11. Nucleosome dynamics regulate Neurospora circadian clock Reviewed

    Hatori, M., Panda, S.

    EMBO Reports   Vol. 14 ( 10 ) page: 854 - 5   2013.10

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    DOI: 10.1038/embor.2013.143

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  12. Small-molecule antagonists of melanopsin-mediated phototransduction Reviewed

    Jones, K.A., Hatori, M., Mure, L.S., Bramley, J.R., Artymyshyn, R., Hong, S.-P., Marzabadi, M., Zhong, H., Sprouse, J., Zhu, Q., Hartwick, A.T.E., Sollars, P.J., Pickard, G.E., Panda, S.

    Nature Chemical Biology   Vol. 9 ( 10 ) page: 630 - 5   2013.10

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    DOI: 10.1038/nchembio.1333

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  13. Aberrant development of the suprachiasmatic nucleus and circadian rhythms in mice lacking the homeodomain protein Six6 Reviewed

    Clark, D.D., Gorman, M.R., Hatori, M., Meadows, J.D., Panda, S., Mellon, P.L.

    Journal of Biological Rhythms   Vol. 28 ( 1 ) page: 15 - 25   2013.2

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    Publishing type:Research paper (scientific journal)   Publisher:SAGE PUBLICATIONS INC  

    The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is the central pacemaker for peripheral and organismal circadian rhythms. The development of this hypothalamic structure depends on genetic programs throughout embryogenesis. We have investigated the role of the homeodomain transcription factor Six6 in the development of the SCN. We first showed that Six6 mRNA has circadian regulation in the mouse SCN. We then characterized the behavioral activity patterns of Six6-null mice under various photoperiod manipulations and stained their hypothalami using SCN-specific markers. Six6-null mice display abnormal patterns of circadian behavior indicative of SCN abnormalities. The ability of light exposure to reset rhythms correlates with the presence or absence of optic nerves, but all Six6-null mice show irregular rhythms. In contrast, wild-type mice with crushed optic nerves maintain regular rhythms regardless of light exposure. Using immunohistochemistry for arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP), and beta-galactosidase, we demonstrated the lack of these SCN markers in all Six6-null mice regardless of the presence of optic nerve or partial circadian rhythms. Therefore, Six6 is required for the normal development of the SCN, and the Six6-null mouse can mount independent, although irregular, circadian rhythms despite the apparent absence of a histochemically defined SCN.

    DOI: 10.1177/0748730412468084

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  14. Biosynthesis and biological actions of pineal neurosteroids in domestic birds Reviewed

    Tsutsui, K., Haraguchi, S., Hatori, M., Hirota, T., Fukada, Y.

    Neuroendocrinology   Vol. 98 ( 2 ) page: 97 - 105   2013

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    Publishing type:Research paper (scientific journal)   Publisher:KARGER  

    The central and peripheral nervous systems have the capacity of synthesizing steroids de novo from cholesterol, the so-called 'neurosteroids'. De novo synthesis of neurosteroids from cholesterol appears to be a conserved property across the subphylum vertebrata. Until recently, it was generally believed that neurosteroids are produced in neurons and glial cells in the central and peripheral nervous systems. However, our recent studies on birds have demonstrated that the pineal gland, an endocrine organ located close to the brain, is an important site of production of neurosteroids de novo from cholesterol. 7 alpha-Hydroxypregnenolone is a major pineal neurosteroid that stimulates locomotor activity of juvenile birds, connecting light-induced gene expression with locomotion. The other major pineal neurosteroid allopregnanolone is involved in Purkinje cell survival by suppressing the activity of caspase-3, a crucial mediator of apoptosis during cerebellar development. This review is an updated summary of the biosynthesis and biological actions of pineal neurosteroids. Copyright (C) 2013 S. Karger AG, Basel

    DOI: 10.1159/000353782

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  15. New biosynthesis and biological actions of avian neurosteroids. Reviewed International journal

    Kazuyoshi Tsutsui, Shogo Haraguchi, Kazuhiko Inoue, Hitomi Miyabara, Takayoshi Ubuka, Megumi Hatori, Tsuyoshi Hirota, Yoshitaka Fukada

    Journal of experimental neuroscience   Vol. 7 ( 1 ) page: 15 - 29   2013

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    De novo neurosteroidogenesis from cholesterol occurs in the brain of various avian species. However, the biosynthetic pathways leading to the formation of neurosteroids are still not completely elucidated. We have recently found that the avian brain produces 7α-hydroxypregnenolone, a novel bioactive neurosteroid that stimulates locomotor activity. Until recently, it was believed that neurosteroids are produced in neurons and glial cells in the central and peripheral nervous systems. However, our recent studies on birds have demonstrated that the pineal gland, an endocrine organ located close to the brain, is an important site of production of neurosteroids de novo from cholesterol. 7α-Hydroxypregnenolone is a major pineal neurosteroid that stimulates locomotor activity of juvenile birds, connecting light-induced gene expression with locomotion. The other major pineal neurosteroid allopregnanolone is involved in Purkinje cell survival during development. This paper highlights new aspects of neurosteroid synthesis and actions in birds.

    DOI: 10.4137/JEN.S11148

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  16. Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines Reviewed

    Narasimamurthy, R., Hatori, M., Nayak, S.K., Liu, F., Panda, S., Verma, I.M.

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 109 ( 31 ) page: 12662 - 7   2012.7

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    Publishing type:Research paper (scientific journal)   Publisher:NATL ACAD SCIENCES  

    Chronic sleep deprivation perturbs the circadian clock and increases susceptibility to diseases such as diabetes, obesity, and cancer. Increased inflammation is one of the common underlying mechanisms of these diseases, thus raising a hypothesis that circadian-oscillator components may regulate immune response. Here we show that absence of the core clock component protein cryptochrome (CRY) leads to constitutive elevation of proinflammatory cytokines in a cell-autonomous manner. We observed a constitutive NF-kappa B and protein kinase A (PKA) signaling activation in Cry1(-/-);Cry2(-/-) cells. We further demonstrate that increased phosphorylation of p65 at S276 residue in Cry1(-/-);Cry2(-/-) cells is due to increased PKA signaling activity, likely induced by a significantly high basal level of cAMP, which we detected in these cells. In addition, we report that CRY1 binds to adenylyl cyclase and limits cAMP production. Based on these data, we propose that absence of CRY protein(s) might release its (their) inhibition on cAMP production, resulting in elevated cAMP and increased PKA activation, subsequently leading to NF-kappa B activation through phosphorylation of p65 at S276. These results offer a mechanistic framework for understanding the link between circadian rhythm disruption and increased susceptibility to chronic inflammatory diseases.

    DOI: 10.1073/pnas.1209965109

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  17. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet Reviewed

    Hatori, M., Vollmers, C., Zarrinpar, A., DiTacchio, L., Bushong, E.A., Gill, S., Leblanc, M., Chaix, A., Joens, M., Fitzpatrick, J.A.J., Ellisman, M.H., Panda, S.

    Cell Metabolism   Vol. 15 ( 6 ) page: 848 - 60   2012.6

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    While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes' expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a non-pharmacological strategy against obesity and associated diseases.

    DOI: 10.1016/j.cmet.2012.04.019

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  18. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β Reviewed

    Cho, H., Zhao, X., Hatori, M., Yu, R.T., Barish, G.D., Lam, M.T., Chong, L.-W., Ditacchio, L., Atkins, A.R., Glass, C.K., Liddle, C., Auwerx, J., Downes, M., Panda, S., Evans, R.M.

    Nature   Vol. 485 ( 7396 ) page: 123 - 7   2012.3

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    Publishing type:Research paper (scientific journal)   Publisher:NATURE PUBLISHING GROUP  

    The circadian clock acts at the genomic level to coordinate internal behavioural and physiological rhythms via the CLOCK-BMAL1 transcriptional heterodimer. Although the nuclear receptors REV-ERB-alpha and REV-ERB-beta have been proposed to form an accessory feedback loop that contributes to clock function(1,2), their precise roles and importance remain unresolved. To establish their regulatory potential, we determined the genome-wide cis-acting targets (cistromes) of both REV-ERB isoforms in murine liver, which revealed shared recognition at over 50% of their total DNA binding sites and extensive overlap with the master circadian regulator BMAL1. Although REV-ERB-alpha has been shown to regulate Bmal1 expression directly(1,2), our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-alpha and REV-ERB-beta genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-alpha and REV-ERB-beta cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-alpha and Rev-erb-beta function by creating double-knockout mice profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, double-knockout mice show markedly altered circadian wheel-running behaviour and deregulated lipid metabolism. These data now unite REV-ERB-alpha and REV-ERB-beta with PER, CRY and other components of the principal feedback loop that drives circadian expression and indicate a more integral mechanism for the coordination of circadian rhythm and metabolism.

    DOI: 10.1038/nature11048

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  19. Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock Reviewed

    DiTacchio, L., Le, H.D., Vollmers, C., Hatori, M., Witcher, M., Secombe, J., Panda, S.

    Science   Vol. 333 ( 6051 ) page: 1881 - 5   2011.9

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    Publishing type:Research paper (scientific journal)   Publisher:AMER ASSOC ADVANCEMENT SCIENCE  

    In animals, circadian oscillators are based on a transcription-translation circuit that revolves around the transcription factors CLOCK and BMAL1. We found that the JumonjiC (JmjC) and ARID domain-containing histone lysine demethylase 1a (JARID1a) formed a complex with CLOCK-BMAL1, which was recruited to the Per2 promoter. JARID1a increased histone acetylation by inhibiting histone deacetylase 1 function and enhanced transcription by CLOCK-BMAL1 in a demethylase-independent manner. Depletion of JARID1a in mammalian cells reduced Per promoter histone acetylation, dampened expression of canonical circadian genes, and shortened the period of circadian rhythms. Drosophila lines with reduced expression of the Jarid1a homolog, lid, had lowered Per expression and similarly altered circadian rhythms. JARID1a thus has a nonredundant role in circadian oscillator function.

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  20. Light-dependent and circadian clock-regulated activation of sterol regulatory element-binding protein, X-box-binding protein 1, and heat shock factor pathways Reviewed

    Hatori, M., Hirota, T., Iitsuka, M., Kurabayashi, N., Haraguchi, S., Kokame, K., Sato, R., Nakai, A., Miyata, T., Tsutsui, K., Fukada, Y.

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 108 ( 12 ) page: 4864 - 9   2011.3

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    Publishing type:Research paper (scientific journal)   Publisher:NATL ACAD SCIENCES  

    The circadian clock is phase-delayed or -advanced by light when given at early or late subjective night, respectively. Despite the importance of the time-of-day-dependent phase responses to light, the underlying molecular mechanism is poorly understood. Here, we performed a comprehensive analysis of light-inducible genes in the chicken pineal gland, which consists of light-sensitive clock cells representing a prototype of the clock system. Light stimulated expression of 62 genes and 40 ESTs by >2.5-fold, among which genes responsive to the heat shock and endoplasmic reticulum stress as well as their regulatory transcription factors heat shock factor (HSF) 1, HSF2, and X-box-binding protein 1 (XBP1) were strongly activated when a light pulse was given at late subjective night. In contrast, the light pulse at early subjective night caused prominent induction of E4bp4, a key regulator in the phase-delaying mechanism of the pineal clock, along with activation of a large group of cholesterol biosynthetic genes that are targets of sterol regulatory element-binding protein (SREBP) transcription factor. We found that the light pulse stimulated proteolytic formation of active SREBP-1 that, in turn, transactivated E4bp4 expression, linking SREBP with the light-input pathway of the pineal clock. As an output of light activation of cholesterol biosynthetic genes, we found light-stimulated pineal production of a neurosteroid, 7 alpha-hydroxypregnenolone, demonstrating a unique endocrine function of the pineal gland. Intracerebroventricular injection of 7 alpha-hydroxypregnenolone activated locomotor activities of chicks. Our study on the genome-wide gene expression analysis revealed time-of-day-dependent light activation of signaling pathways and provided molecular connection between gene expression and behavior through neurosteroid release from the pineal gland.

    DOI: 10.1073/pnas.1015959108

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  21. Melanopsin Contributions to Irradiance Coding in the Thalamo-Cortical Visual System Reviewed

    Timothy M. Brown, Carlos Gias, Megumi Hatori, Sheena R. Keding, Ma'ayan Semo, Peter J. Coffey, John Gigg, Hugh D. Piggins, Satchidananda Panda, Robert J. Lucas

    PLOS BIOLOGY   Vol. 8 ( 12 ) page: e1000558   2010.12

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    Publishing type:Research paper (scientific journal)   Publisher:PUBLIC LIBRARY SCIENCE  

    Photoreception in the mammalian retina is not restricted to rods and cones but extends to a subset of retinal ganglion cells expressing the photopigment melanopsin (mRGCs). These mRGCs are known to drive such reflex light responses as circadian photoentrainment and pupillomotor movements. By contrast, until now there has been no direct assessment of their contribution to conventional visual pathways. Here, we address this deficit. Using new reporter lines, we show that mRGC projections are much more extensive than previously thought and extend across the dorsal lateral geniculate nucleus (dLGN), origin of thalamo-cortical projection neurons. We continue to show that this input supports extensive physiological light responses in the dLGN and visual cortex in mice lacking rods+cones (a model of advanced retinal degeneration). Moreover, using chromatic stimuli to isolate melanopsin-derived responses in mice with an intact visual system, we reveal strong melanopsin input to the similar to 40% of neurons in the LGN that show sustained activation to a light step. We demonstrate that this melanopsin input supports irradiance-dependent increases in the firing rate of these neurons. The implication that melanopsin is required to accurately encode stimulus irradiance is confirmed using melanopsin knockout mice. Our data establish melanopsin-based photoreception as a significant source of sensory input to the thalamo-cortical visual system, providing unique irradiance information and allowing visual responses to be retained even in the absence of rods+cones. These findings identify mRGCs as a potential origin for aspects of visual perception and indicate that they may support vision in people suffering retinal degeneration.

    DOI: 10.1371/journal.pbio.1000558

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  22. CRY links the circadian clock and CREB-mediated gluconeogenesis. Reviewed

    Hatori, M., Panda, S.

    Cell research   Vol. 20 ( 12 ) page: 1285 - 8   2010.12

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    Publishing type:Research paper (scientific journal)   Publisher:INST BIOCHEMISTRY & CELL BIOLOGY  

    DOI: 10.1038/cr.2010.152

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  23. The emerging roles of melanopsin in behavioral adaptation to light Reviewed

    Megumi Hatori, Satchidananda Panda

    TRENDS IN MOLECULAR MEDICINE   Vol. 16 ( 10 ) page: 435 - 46   2010.10

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    Publisher:ELSEVIER SCI LTD  

    The adaptation of behavior and physiology to changes in the ambient light level is of crucial importance to life. These adaptations include the light modulation of neuroendocrine function and temporal alignment of physiology and behavior to the day:night cycle by the circadian clock. These non-image-forming (NIF) responses can function independent of rod and cone photoreceptors but depend on ocular light reception, suggesting the participation of novel photoreceptors in the eye. The discovery of melanopsin in intrinsically photosensitive retinal ganglion cells (ipRGCs) and genetic proof for its important role in major NIF responses have offered an exciting entry point to comprehend how mammals adapt to the light environment. Here, we review the recent advances in our understanding of the emerging roles of melanopsin and ipRGCs. These findings now offer new avenues to understand the role of ambient light in sleep, alertness, dependent physiologies and potential pharmacological intervention as well as lifestyle modifications to improve the quality of life.

    DOI: 10.1016/j.molmed.2010.07.005

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  24. Inducible Ablation of Melanopsin-Expressing Retinal Ganglion Cells Reveals Their Central Role in Non-Image Forming Visual Responses Reviewed

    Megumi Hatori, Hiep Le, Christopher Vollmers, Sheena Racheal Keding, Nobushige Tanaka, Christian Schmedt, Timothy Jegla, Satchidananda Panda

    PLOS ONE   Vol. 3 ( 6 ) page: e2451   2008.6

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    Publishing type:Research paper (scientific journal)   Publisher:PUBLIC LIBRARY SCIENCE  

    Rod/cone photoreceptors of the outer retina and the melanopsin-expressing retinal ganglion cells ( mRGCs) of the inner retina mediate non-image forming visual responses including entrainment of the circadian clock to the ambient light, the pupillary light reflex ( PLR), and light modulation of activity. Targeted deletion of the melanopsin gene attenuates these adaptive responses with no apparent change in the development and morphology of the mRGCs. Comprehensive identification of mRGCs and knowledge of their specific roles in image-forming and non-image forming photoresponses are currently lacking. We used a Cre-dependent GFP expression strategy in mice to genetically label the mRGCs. This revealed that only a subset of mRGCs express enough immunocytochemically detectable levels of melanopsin. We also used a Cre-inducible diphtheria toxin receptor ( iDTR) expression approach to express the DTR in mRGCs. mRGCs develop normally, but can be acutely ablated upon diphtheria toxin administration. The mRGC-ablated mice exhibited normal outer retinal function. However, they completely lacked non-image forming visual responses such as circadian photoentrainment, light modulation of activity, and PLR. These results point to the mRGCs as the site of functional integration of the rod/cone and melanopsin phototransduction pathways and as the primary anatomical site for the divergence of image-forming and non-image forming photoresponses in mammals.

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  25. Lcg is a light-inducible and clock-controlled gene expressed in the chicken pineal gland Reviewed

    M Hatori, T Okano, Y Nakajima, M Doi, Y Fukada

    JOURNAL OF NEUROCHEMISTRY   Vol. 96 ( 6 ) page: 1790 - 800   2006.3

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    Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

    The circadian clock is an autonomous biological clock that is entrainable to environmental 24-h cycles by receiving time cues such as light. Generally, light given at early and late subjective night, respectively, delays and advances the phase of the circadian oscillator. We previously searched for the chicken pineal genes that are induced by light in a phase-dependent manner. The present study undertook cDNA cloning and characterization of a gene whose expression was remarkably up-regulated by light at late subjective night. The mRNA level of this gene exhibited robust diurnal change in the pineal gland, with a peak in the early (subjective) day under light-dark cycles and constant dark condition, and hence it was designated Lcg (Light-inducible and Clock-controlled Gene). Chicken Lcg encodes a coiled-coil protein composed of 560 amino acid residues. Among chicken tissues, the pineal gland and the retina exhibited relatively high expression levels of LCG. LCG was colocalized with gamma-tubulin, a centrosomal protein, when expressed in COS7 cells, and LCG is the first example of a clock-related molecule being accumulated at the centrosome. Coimmunoprecipitation of LCG with gamma-tubulin in the chicken pineal lysate suggests a link between the circadian oscillator and the centrosomal function.

    DOI: 10.1111/j.1471-4159.2006.03712.x

    Web of Science

    PubMed

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MISC 7

  1. 眼疾患への抗加齢アプローチ ドライアイから網膜色素変性、近視まで

    坪田 一男, 根岸 一乃, 榛村 重人, 小川 葉子, 村戸 ドール, 羽藤 晋, 小沢 洋子, 綾木 雅彦, 中村 滋, 川島 素子, 栗原 俊英, 羽鳥 恵, 川北 哲也, 樋口 明弘, 井上 佐智子, 海道 美奈子, 石田 玲子, Connell Samuel, Vu Chi Hoang Viet, Ibrahim Osama, Mohamed Aly, 久村 隆二, 今田 敏博, 稲葉 隆明, 泉田 祐輔, 小島 隆司, きん 楷, 向井 慎, 佐野 こころ, 柳 櫻, 比嘉 一成, 稲垣 絵海, 鳥居 秀成, 堅田 侑作, 三輪 幸裕, 森 紀和子, 姜 效炎, 篠田 肇, 永井 紀博, 久保田 俊介, 久保田 みゆき, 芝 大介, 結城 賢弥, 内田 敦郎, 成松 俊雄, 伴 紀充, 鴨下 衛, 戸田 郁子, 井手 武, 三木 恵美子, 荒井 宏幸, 加藤 圭一, 原 裕, 原 道子, 渡辺 光博, 福田 真嗣, 山中 章弘, 世古 裕子, 中村 孝博, Apte Rajendra, Lin Jonathan, 今井 眞一郎

    日本眼科学会雑誌   Vol. 121 ( 3 ) page: 232 - 248   2017.3

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    Language:Japanese   Publisher:(公財)日本眼科学会  

    緑内障,加齢黄斑変性をはじめとしてドライアイなど眼疾患の大部分は加齢によって罹患率が上昇する加齢関連疾患である.また網膜色素変性症や近視も遺伝の素因があるものの,加齢によって病態が進行することから加齢関連疾患ともいえる.そこで個々の疾患一つひとつをターゲットにするのではなく,加齢そのものにチャレンジして結果的に眼疾患を治療するという新たなアプローチが始まっている.現在の抗加齢アプローチの基本はカロリー制限(CR)であり,さまざまなメカニズムを介して抗酸化酵素など長寿にプラスになる遺伝子群の誘導を行い健康にプラスに働くと考えられている.まずは酸化ストレスと眼疾患の関係だが,Cu,Zn-superoxide dismutase-1(Sod-1)ノックアウトマウス,Mev1トランスジェニックマウス,Nrf-2ノックアウトマウスなど酸化ストレスが増大する遺伝子改変マウスや,喫煙などの酸化ストレス増大状態では,涙液分泌が減少しドライアイを発症することを確認した.近年,マイクロバイオームが注目を集めているが,ドライアイ研究においてもラクトフェリンや乳酸菌サプリメントなどによって涙腺の酸化ストレスを減少させることが分かり,涙液を増大させるサプリメントとして臨床に使われるようになった.CRによって長寿遺伝子サーチュインが活性化するが,CRによって涙液分泌が増大し,またサーチュインを活性化するレスベラトロールやnicotinamide mononucleotide(NMN)によって網膜保護が可能なことを示した.特にNMNについては網膜色素変性症の抑制に効果がある可能性があり期待されている.また,CRの第2の経路といわれるケトン体点眼薬を開発したところCRと同じ効果があることが分かり,新しいドライアイ治療法や網膜,視神経の保護薬として臨床開発中である.その他の経路としては免疫老化の観点から小胞体ストレスの抑制,低酸素誘導因子(HIF)の抑制,インスリン様成長因子(IGF)経路の抑制などがあり,これらのすべての経路を介するアンチエイジングアプローチが始まっている.以上のように抗加齢という新しい戦略による眼疾患へのアプローチが始まりつつある.現在の医療費増大に対して予防医学の導入が叫ばれて久しいが,抗加齢アプローチはまさに加齢に注目した次世代の予防医学と考えられ,大きな期待が寄せられている.(著者抄録)

  2. [Aging and homeostasis. Circadian rhythms and aging.]

    Hatori M

    Clinical calcium   Vol. 27 ( 7 ) page: 955 - 961   2017

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  3. ニワトリ松果体で光誘導される遺伝子群の同定とその生理的役割の解析

    飯塚倫子, 倉林伸博, 羽鳥恵, 原口省吾, 筒井和義, 深田吉孝

    日本比較生理生化学会大会予稿集   Vol. 31st   page: 64   2009

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    Language:Japanese  

    J-GLOBAL

  4. ニワトリ松果体におけるコレステロール合成系酵素群の遺伝子発現解析

    飯塚倫子, 倉林伸博, 羽鳥恵, 広田毅, 原口省吾, 筒井和義, 深田吉孝

    日本比較生理生化学会大会予稿集   Vol. 30th   page: 23   2008

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    Language:Japanese  

    J-GLOBAL

  5. A clock-related gene Lcg expressed in the chicken pineal gland

    Megumi Hatori, Toshiyuki Okano, Yoshito Nakajima, Masao Doi, Yoshitaka Fukada

    ZOOLOGICAL SCIENCE   Vol. 22 ( 12 ) page: 1490 - 1490   2005.12

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:ZOOLOGICAL SOC JAPAN  

    Web of Science

  6. 【シグナル伝達研究2005-'06 生命現象や疾患を支配する分子メカニズムと新しい研究法 現在と未来】生命の形と機能を司るシグナル伝達 生物時計システムにおけるリン酸化の役割

    深田 吉孝, 羽鳥 恵

    実験医学   Vol. 23 ( 11 ) page: 1755 - 1761   2005.6

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    Language:Japanese   Publisher:(株)羊土社  

    生物は体内に時計をもっている.体内時計の中でも,約1日周期のリズム(概日リズム)を刻む時計は概日時計と呼ばれる.概日時計は自律的に発振するだけでなく,光などの外界の環境変動を巧みに利用して時刻合わせを行っている.概日時計の発振は時計遺伝子群が織りなすフィードバックループによって構成され,時計発振や光応答には時計タンパク質のリン酸化が深く関与している.本稿ではタンパク質キナーゼの役割を中心に,概日時計の分子機構を概説する(著者抄録)

  7. 生物時計システムにおけるリン酸化の役割 実験医学, 増刊号『シグナル伝達研究2005-06』

    深田吉孝, 羽鳥恵

    羊土社   Vol. 23 ( 11 ) page: 137 - 143   2005

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KAKENHI (Grants-in-Aid for Scientific Research) 4

  1. 非視覚光応答による肥満代謝制御

    Grant number:19K22693  2019.6 - 2021.3

    挑戦的研究(萌芽)

    羽鳥 恵

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    Authorship:Principal investigator 

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

    生物は睡眠・覚醒や体温、代謝など、一日周期で様々な生体反応を示す。それらの概日リズムを制御する体内時計が概日時計である。概日時計の周期は正確に24時間ではない。そのため哺乳類の概日時計システムは、外界環境からの刺激を利用して日々の時刻のずれの補正を行っている。最も重要な時計調節因子は、光と食事である。本研究では両因子がいかに相互作用して生体の恒常性維持に寄与するかの解明を目指す。
    目に存在する光受容細胞は視細胞層を構成する桿体・錐体だけではない。哺乳類の網膜神経節細胞の2-3%は青色光感受性GPCRであるメラノプシンを発現している。Melanopsin-expressing RGC(mRGC)は桿体・錐体に次ぐ第三の光受容細胞として、概日時計の光応答や瞳孔収縮などの視覚以外の光応答、すなわち非視覚応答を引き起こす。桿体・錐体は100年に渡る研究の蓄積があるのに対し、メラノプシンは発見されてから15年程度しか経っておらず、その分子機能と制御機構を明らかにすることは他のGPCRとの差、つまり受容体としての性質の理解につながる。光環境の変化による概日時計の攪乱は鬱や肥満症など多様な疾患と関連しており、メラノプシンの理解はこれらの疾患の予防と治療にもつながると期待できる。さらに、メラノプシン遺伝子破壊マウスを用いた解析により睡眠、学習や気分への関与が報告されている。ごく最近になり日常生活に普及した白色LEDの主成分は青色であり、青色光が健康状態に与える影響の理解は喫緊の課題である。感覚機能は古典的に視覚・聴覚・触覚・味覚・嗅覚に分類されるが、「無意識の感覚」である非視覚応答を理解したい。一方、時計振幅を増大させる目的でマウスの摂食時間を8時間に制限したところ、食事量を減らすことなく肥満や関連する病態が防がれた(時間制限摂食;Cell Metab 2012等)。本申請では光と食の両入力因子の相互作用について、非視覚応答が概日時計を介して肥満代謝に影響を与える可能性の検証に挑戦している。
    メラノプシン破壊マウスを食事誘導性肥満の条件下に置き、野生型マウスと効果を比較したところ、メラノプシンの肥満への影響を示す重要なデータを得ることができた。
    光と食事の統合的な研究は未開拓分野であり、両者がどのような相互作用により時計及び代謝を制御しているのか、恒常性維持ネットワークの解明を目指す。中枢と末梢の時計相互作用、および非視覚光応答と代謝制御における新しい概念を提供する。

  2. 昼行性生物と夜行性生物における概日光受容体メラノプシンの機能解析

    Grant number:19H03266  2019.4 - 2022.3

    羽鳥 恵

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    Authorship:Principal investigator 

    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

    目に存在する光受容細胞は桿体・錐体だけではない。網膜神経節に存在する一部の細胞は光受容タンパク質であるメラノプシンを発現し、概日時計の光応答や瞳孔収縮などの視覚以外の光応答、すなわち非視覚応答を引き起こす。メラノプシンを最も感度よく活性化させるのはブルーライトである。これまでの基礎研究は主に、夜行性であるマウスを用いて行われてきた。地球上にはヒトをはじめとする昼行性動物も存在し、光の効果は両者で大きく異なる。そこで、ヒトの健康へ研究を応用することを見据え、昼行性霊長類も用いてメラノプシンの機能理解に挑む。
    日常生活で意識することは少ないかもしれないが、見ること、つまり視覚応答以外にも生物は光に応答している。例えば概日時計の光応答や瞳孔収縮などの視覚以外の光応答などをまとめて、非視覚応答と呼ぶ。哺乳類の網膜神経節細胞の2-3%は青色光感受性GPCRであるメラノプシンを発現しており、Melanopsin-expressing RGC(mRGC)は桿体・錐体に次ぐ第三の光受容細胞として機能している。現代社会において夜間の光暴露は避けられない。不適切な時間、つまり夜間の寝る直前のブルーライトは概日時計の乱れを引き起こす。概日リズムの乱れは睡眠や鬱、癌の発症などと関連する。つまり、青色光を特に感度良く感じる概日光受容分子メラノプシンの分子理解は、これらの疾患や不調の改善、ひいては特に高齢化社会において生活の質と健康の促進に役立つ。mRGCは網膜の中でも脳への情報伝達の最終段階である神経節細胞の一部である。なぜ神経節細胞に光受容能が存在するのか、さらに、形態の違いよって数十種類以上に分類される神経節細胞の内、なぜごく一部の細胞だけが非視覚応答に特化した機能を有するのかはわかっていない。メラノプシンは桿体・錐体のオプシンと比べて明るい光に反応し、活性を持続するユニークな光受容体である。これらの特性を規定するメカニズムの解明を目指し、メラノプシン分子の性質および細胞特異性に着目してこれまでに、リン酸化制御と光応答の終了過程を明らかにした(Neuron 2016、Cell Reports 2018など)。これらの知見を発展させ、応答の開始機構および他の網膜神経節細胞との差異を解明に取り組んでいる。
    本研究ではメラノプシン発現網膜神経節細胞特異的に発現する分子群を見出し、細胞特異的なメラノプシンの発現や機能の制御機構を明らかにする。mRGCは形態から数種類のサブタイプの存在が報告されている。これまでに、マウスのメラノプシン発現網膜神経節細胞をサブタイプ別に採取し、網羅的遺伝子発現解析に供した。
    mRGCに発現する遺伝子群を単離し、それらの解析より光応答の開始機構および細胞を規定する機構を明らかにする。

  3. Roles of a circadian photopigment melanopsin in mammals

    Grant number:16H06174  2016.4 - 2019.3

    Hatori Megumi

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    Authorship:Principal investigator 

    Grant amount:\24310000 ( Direct Cost: \18700000 、 Indirect Cost:\5610000 )

    In mammalian retinas, there are three photoreceptors: rods, cones and melanopsin-expressing retinal ganglion cells. Rods and cones are responsible for image forming vision. In contrast, melanopsin-expressing retinal ganglion cells contribute to non-image forming visions, such as circadian photoentrainment and pupil constriction. Melanopsin is a GPCR which can be activated by 460-480 nm light, and its light response properties are different from those of rods and cones. We had revealed phosphorylation of and Arrestin binding to the C-terminus cytosolic region of melanopsin is responsible for the shut-off mechanism after light pulse.

  4. Molecular mechanism of melanopsin to induce non-image forming responses

    Grant number:26891022  2014.8 - 2016.3

    Hatori Megumi

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    Authorship:Principal investigator 

    Grant amount:\2730000 ( Direct Cost: \2100000 、 Indirect Cost:\630000 )

    Melanopsin photopigment expressed in intrinsically photosensitive retinal ganglion cells plays a crucial role in the adaptation of mammals to ambient light environment through both image-forming and non-image-forming visual responses. The melanopsin-expressing retinal ganglion cells are structurally and functionally distinct from classical rod/cone photoreceptors and have unique properties, including single-photon response, long response latency, photon integration over time, and slow deactivation. To understand the molecular property of melanospin, I generated various mutant versions of melanopsin, and these proteins were expressed in mammalian cells. Blue light-dependent increases in cytosolic calcium were monitored. By using this assay system, several of mutant melanopsin were obtained to show in vitro response difference compared to wild type melanopsin, and the effect of these mutant melanopsin on non-image forming responses will be evaluated in vivo in mice.