Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/s0960-9822(02)01034-5

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The circadian clock is a biological timekeeping system that oscillates with a circa-24-h period, reset by environmental timing cues, especially light, to the 24-h day-night cycle. In mammals, a "central" clock in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes "peripheral" clocks throughout the body to regulate behavior, metabolism, and physiology. A key feature of the clock's oscillation is resistance to abrupt perturbations, but the mechanisms underlying such robustness are not well understood. Here, we probe clock robustness to unexpected photic perturbation by measuring the speed of reentrainment of the murine locomotor rhythm after an abrupt advance of the light-dark cycle. Using an intersectional genetic approach, we implicate a critical role for arginine vasopressin pathways, both central within the SCN and peripheral from the anterior pituitary.

DOI： 10.1073/pnas.2308489120

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Language：Japanese   Publisher：(株)北隆館  

海外旅行で異なる明暗環境に瞬時に移動したときに経験する生体リズム異常,いわゆる「時差ぼけ」は,ヒトが生物として直面した現代病の1つである。時差ぼけには,夜型生活をはじめとする近年の急激なライフスタイルの変化にともなう心身の異常や生活習慣病のリスクの増大と共通の誘因メカニズムが関与すると考えられ,その分子機構の解明が待たれる。本稿においては,マウスの時差ぼけモデルにおける分子神経機構,時差の生体への深刻な影響,さらにバソプレッシン神経伝達関連薬の時差ぼけ治療薬としての可能性について述べる。(著者抄録)

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Body temperature in homeothermic animals does not remain constant but displays a regular circadian fluctuation within a physiological range (e.g., 35°C-38.5°C in mice), constituting a fundamental systemic signal to harmonize circadian clock-regulated physiology. Here, we find the minimal upstream open reading frame (uORF) encoded by the 5' UTR of the mammalian core clock gene Per2 and reveal its role as a regulatory module for temperature-dependent circadian clock entrainment. A temperature shift within the physiological range does not affect transcription but instead increases translation of Per2 through its minimal uORF. Genetic ablation of the Per2 minimal uORF and inhibition of phosphoinositide-3-kinase, lying upstream of temperature-dependent Per2 protein synthesis, perturb the entrainment of cells to simulated body temperature cycles. At the organismal level, Per2 minimal uORF mutant skin shows delayed wound healing, indicating that uORF-mediated Per2 modulation is crucial for optimal tissue homeostasis. Combined with transcriptional regulation, Per2 minimal uORF-mediated translation may enhance the fitness of circadian physiology.

DOI： 10.1016/j.celrep.2023.112157

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DOI： 10.1016/j.jtos.2022.10.002

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Calcium signaling is pivotal to the circadian clockwork in the suprachiasmatic nucleus (SCN), particularly in rhythm entrainment to environmental light-dark cycles. Here, we show that a small G-protein Gem, an endogenous inhibitor of high-voltage-activated voltage-dependent calcium channels (VDCCs), is rapidly induced by light in SCN neurons via the calcium (Ca2+)-mediated CREB/CRE transcriptional pathway. Gem attenuates light-induced calcium signaling through its interaction with VDCCs. The phase-shift magnitude of locomotor activity rhythms by light, at night, increases in Gem-deficient (Gem-/-) mice. Similarly, in SCN slices from Gem-/- mice, depolarizing stimuli induce larger phase shifts of clock gene transcription rhythms that are normalized by the application of an L-type VDCC blocker, nifedipine. Voltage-clamp recordings from SCN neurons reveal that Ca2+ currents through L-type channels increase in Gem-/- mice. Our findings suggest that transcriptionally activated Gem feeds back to suppress excessive light-evoked L-type VDCC activation, adjusting the light-induced phase-shift magnitude to an appropriate level in mammals.

DOI： 10.1016/j.celrep.2022.110844

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD⁺)-dependent circadian 3β-hydroxyl-steroid dehydrogenase (3β-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3β-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3β-HSD activity by boosting its coenzyme NAD⁺ availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3β-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction.

DOI： 10.1038/s43587-021-00167-8

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Other Link： https://www.nature.com/articles/s43587-021-00167-8

Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science (PLoS)  

Circadian clocks orchestrate multiple different physiological rhythms in a well-synchronized manner. However, how these separate rhythms are interconnected is not exactly understood. Here, we developed a method that allows for the real-time simultaneous measurement of locomotor activity and body temperature of mice using infrared video camera imaging. As expected from the literature, temporal profiles of body temperature and locomotor activity were positively correlated with each other. Basically, body temperatures were high when animals were in locomotion. However, interestingly, increases in body temperature were not always associated with the appearance of locomotor activity. Video imaging revealed that mice exhibit non-locomotor activities such as grooming and postural adjustments, which alone induce considerable elevation of body temperature. Noticeably, non-locomotor movements always preceded the initiation of locomotor activity. Nevertheless, non-locomotor movements were not always accompanied by locomotor movements, suggesting that non-locomotor movements provide a mechanism of thermoregulation independent of locomotor activity. In addition, in the current study, we also report the development of a machine learning-based recording method for the detection of circadian feeding and drinking behaviors of mice. Our data illustrate the potential utility of thermal video imaging in the investigation of different physiological rhythms.

DOI： 10.1371/journal.pone.0252447

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

<jats:title>Abstract</jats:title><jats:p>G-protein-coupled receptors (GPCRs) are important drug targets with diverse therapeutic applications. However, there are still more than a hundred orphan GPCRs, whose protein functions and biochemical features remain unidentified. <jats:italic>Gpr176</jats:italic> encodes a class-A orphan GPCR that has a role in circadian clock regulation in mouse hypothalamus and is also implicated in human breast cancer transcriptional response. Here we show that Gpr176 is <jats:italic>N</jats:italic>-glycosylated. Peptide-<jats:italic>N</jats:italic>-glycosidase treatment of mouse hypothalamus extracts revealed that endogenous Gpr176 undergoes <jats:italic>N</jats:italic>-glycosylation. Using a heterologous expression system, we show that <jats:italic>N</jats:italic>-glycosylation occurs at four conserved asparagine residues in the N-terminal region of Gpr176. Deficient <jats:italic>N</jats:italic>-glycosylation due to mutation of these residues reduced the protein expression of Gpr176. At the molecular function level, Gpr176 has constitutive, agonist-independent activity that leads to reduced cAMP synthesis. Although deficient <jats:italic>N</jats:italic>-glycosylation did not compromise this intrinsic activity, the resultant reduction in protein expression was accompanied by attenuation of cAMP-repressive activity in the cells. We also demonstrate that human GPR176 is <jats:italic>N</jats:italic>-glycosylated. Importantly, missense variations in the conserved <jats:italic>N</jats:italic>-glycosylation sites of human GPR176 (rs1473415441; rs761894953) affected <jats:italic>N</jats:italic>-glycosylation and thereby attenuated protein expression and cAMP-repressive activity in the cells. We show that <jats:italic>N</jats:italic>-glycosylation is a prerequisite for the efficient protein expression of functional Gpr176/GPR176.</jats:p>

DOI： 10.1038/s41598-020-61370-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Non-coding cis-regulatory elements are essential determinants of development, but their exact impacts on behavior and physiology in adults remain elusive. Cis-element-based transcriptional regulation is believed to be crucial for generating circadian rhythms in behavior and physiology. However, genetic evidence supporting this model is based on mutations in the protein-coding sequences of clock genes. Here, we report generation of mutant mice carrying a mutation only at the E'-box cis-element in the promoter region of the core clock gene Per2. The Per2 E'-box mutation abolishes sustainable molecular clock oscillations and renders circadian locomotor activity and body temperature rhythms unstable. Without the E'-box, Per2 messenger RNA and protein expression remain at mid-to-high levels. Our work delineates the Per2 E'-box as a critical nodal element for keeping sustainable cell-autonomous circadian oscillation and reveals the extent of the impact of the non-coding cis-element in daily maintenance of animal locomotor activity and body temperature rhythmicity.

DOI： 10.1038/s41467-019-10532-2

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Other Link： http://www.nature.com/articles/s41467-019-10532-2

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

Almost all organisms on Earth have an internal biological clock, known as the circadian clock. This clock system drives robust oscillations in metabolism, physiology, and behavior, such as hormone secretions, blood pressure, and sleep/wake cycles, with a period of approximately 24 h. In mammals, circadian rhythms are generated by a timing system comprised of a master pacemaker located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, which orchestrates the clocks in the peripheral tissues. Jet lag, caused by an abrupt change of environmental light-dark cycles, induces a temporal misalignment of the output signal from SCN. We revealed that arginine vasopressin/V1 receptor signaling in the SCN plays a critical role in the resilience of the circadian clock to jet lag. I here discuss a model of SCN neuronal system under a jet lag condition.

DOI： 10.1016/J.NEURES.2017.10.007

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Publishing type：Research paper (scientific journal)   Publisher：Biomedical Research Press  

DOI： 10.2220/biomedres.39.57

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Histochemistry & Cytochemistry  

DOI： 10.1267/ahc.18001

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal-regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway.

DOI： 10.1038/s41467-017-02207-7

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Other Link： http://www.nature.com/articles/s41467-017-02207-7

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/srep46702

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Other Link： http://www.nature.com/articles/srep46702

Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Among nonphotic stimulants, a classic cholinergic agonist, carbachol, is known to have a strong and unique phase-resetting effect on the circadian clock: Intracerebroventricular carbachol treatment causes phase delays during the subjective early night and phase advances in the subjective late night, but the effects of this drug on the suprachiasmatic nucleus (SCN) in vivo and in vitro are still controversial. In the present study, we succeeded in reproducing the biphasic phase-shifting effect of carbachol on clock gene expression in organotypic SCN slices prepared from mice carrying a Per1-promoter fused luciferase gene ( Per1-luc). Since this biphasic effect of carbachol in Per1-luc SCN was prevented by atropine but not by mecamylamine, we concluded that these phase shifts were muscarinic receptor–dependent. Next, we analyzed the expression of muscarinic receptors in the SCN by in situ hybridization and found that M3 and M4 subtypes were expressed in SCN cells. These signals appeared neonatally and reached adult levels at postnatal day 10. Together, these findings suggest that carbachol has a phase-dependent phase-shifting effect on the SCN clock through muscarinic receptor subtypes expressed in the SCN.

DOI： 10.1177/0748730417691205

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/0748730417691205

Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Measuring real-time gene activity in the brains of freely moving animals presents a challenging issue in neuroscience research. Circadian gene expression in neurons of the suprachiasmatic nucleus (SCN), a small nucleus in the hypothalamus, is reflected in behavioral rhythmicity. Cellular oscillatory gene expression is generated by a transcription-translation feedback loop of clock genes including 2 oscillatory genes, Per1 and Per2. Here we have succeeded in real-time monitoring of Per1 and Per2 transcription separately by detecting the bioluminescence of luciferase ( luc) reporters using a plastic optical fiber inserted into the SCN of freely moving rats. Per1-luc and Per2-luc rhythms peaked in the middle and late subjective day, respectively, which was confirmed by quantitative PCR-based measurements of SCN tissue samples. Studies of in vivo transcriptional states of clock genes in freely moving animals should improve our understanding of how clock gene expression is reflected in behavior.

DOI： 10.1177/0748730415621412

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/0748730415621412

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

DOI： 10.1038/srep11780

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Pharmaceutical Society of Japan  

The endogenous circadian clock drives robust oscillations in physiology and behavior, such as hormone secretions and sleep/wake cycles, with a period of about 24 h. We are rarely aware of this internal clock system because it is usually synchronized with environmental light-dark cycles. However, travelling rapidly across multiple time zones in a jet airplane suddenly makes us aware of the desynchrony between the body clock and external time, causing sleep disturbances and gastrointestinal problems. Although jet lag is recognized as a chronobiological problem, its specific molecular and neural mechanisms are poorly understood. To address this issue, we identified genes highly expressed in the suprachiasmatic nucleus of the anterior hypothalamus (SCN), the mammalian master clock that controls rhythmic behavior, then analyzed the behavior of knock-out mice for these genes under jet lag condition. We found that the circadian rhythms of locomotor activity and clock gene expression rapidly re-entrained to phase-shifted light-dark cycles in mice genetically deficient in V1a and V1b receptors. Real-time imaging of cellular rhythms in the SCN suggested that interneuronal communication through V1a and V1b confers on the SCN an intrinsic resistance to external perturbation, enhancing the robustness of the SCN clockwork. Pharmacological blockade of V1a and V1b in the SCN of wild-type mice accelerated their recovery from jet lag symptoms, suggesting vasopressin signaling as a potential pharmaceutical intervention for the management of circadian rhythm misalignment.

DOI： 10.1248/yakushi.15-00206

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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<title>Abstract</title>
Inhibition of Nogo-66 receptor (NgR) can promote recovery following spinal cord injury. The ecto-domain of NgR can be phosphorylated by protein kinase A (PKA), which blocks activation of the receptor. Here, we found that infusion of PKA plus ATP into the damaged spinal cord can promote recovery of locomotor function. While significant elongation of cortical-spinal axons was not detectable even in the rats showing enhanced recovery, neuronal precursor cells were observed in the region where PKA plus ATP were directly applied. NgR1 was expressed in neural stem/progenitor cells (NSPs) derived from the adult spinal cord. Both an NgR1 antagonist NEP1-40 and ecto-domain phosphorylation of NgR1 promote neuronal cell production of the NSPs, in vitro. Thus, inhibition of NgR1 in NSPs can promote neuronal cell production, which could contribute to the enhanced recovery of locomotor function following infusion of PKA and ATP.

DOI： 10.1038/srep04972

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Other Link： http://www.nature.com/articles/srep04972

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Biochemical Society  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

The eukaryotic biological clock involves a negative transcription-translation feedback loop in which clock genes regulate their own transcription and that of output genes of metabolic significance. While around 10% of the liver transcriptome is rhythmic, only about a fifth is driven by de novo transcription, indicating mRNA processing is a major circadian component. Here, we report that inhibition of transmethylation reactions elongates the circadian period. RNA sequencing then reveals methylation inhibition causes widespread changes in the transcription of the RNA processing machinery, associated with m(6)A-RNA methylation. We identify m(6)A sites on many clock gene transcripts and show that specific inhibition of m(6)A methylation by silencing of the m(6)A methylase Mettl3 is sufficient to elicit circadian period elongation and RNA processing delay. Analysis of the circadian nucleocytoplasmic distribution of clock genes Per2 and Arntl then revealed an uncoupling between steady-state pre-mRNA and cytoplasmic mRNA rhythms when m(6)A methylation is inhibited.

DOI： 10.1016/j.cell.2013.10.026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/ncomms1316

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Other Link： http://www.nature.com/articles/ncomms1316

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

To ensure the maintenance of tissues in mammals, cell loss must be balanced with cell production, the proliferative activity being different from tissue to tissue. In this article, the authors propose a new method for the quantification of the proliferative activity, defined as the S-phase fraction of actively cycling cells, by dual labeling with fluorescence and peroxidase immunohistochemistry using BrdU (marker of S-phase) and Ki67 antibodies (marker of G₁-, S-, G₂-, and M-phases) after a one-step antigen retrieval. In the generative cell zones of fundic and pyloric glandular stomachs, where the majority of cells were cycling, the authors measured a proliferative activity of 31%. In the epithelium of the forestomach and the skin, where cycling cells are intermingled with G₀ and differentiated cells, proliferative activities were 21% and 13%, respectively. In the adrenal cortex, in which cycling cells were sparsely distributed, the proliferative activity reached 32%. During the regenerative process in the skin after a lesion, the proliferative activity increased in proximity to the wound. The present one-step dual-labeling method has revealed that the proliferative activity is different between tissues and depends on the physiological or pathological state.

DOI： 10.1369/0022155411411090

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1369/0022155411411090

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

DOI： 10.1002/cne.22600

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DOI： 10.1007/s11906-011-0181-3

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Other Link： http://link.springer.com/article/10.1007/s11906-011-0181-3/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.addr.2010.06.004

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science (PLoS)  

DOI： 10.1371/journal.pone.0010951

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DOI： 10.1038/jid.2008.345

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Biomedical Research Press  

Renal tubular NHE3, the Na<SUP>+</SUP>/H<SUP>+</SUP> exchanger, is a critical enzyme for electrolyte and acid-base homeostasis in the kidney. We previously demonstrated that the expression of this gene in the kidney followed a circadian rhythm directly regulated by clock genes acting on E-box elements present on its promoter region. In the present study, we further characterize the circadian expression of NHE3 in the mice kidney by <I>in situ</I> hybridization, and refine quantification of gene expression using real-time PCR combined with laser capture micro-dissection. We show NHE3 mRNA was strongly expressed in the inner stripe of the outer medulla and weakly in the cortex. Further realtime PCR data from dissected medullary nephron demonstrated clear circadian oscillations in the thick ascending limbs and the thin descending limbs, but not in the collecting ducts. The circadian changes of this molecule in the renal medulla may partially contribute to the circadian change of urinary electrolyte secretion.

DOI： 10.2220/biomedres.30.87

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.1016/j.bbrc.2005.05.023

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1074/jbc.m301409200

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1074/jbc.m100254200

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DOI： 10.1074/jbc.m008546200

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Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

<title>ABSTRACT</title>
The Rho family of small GTPases has been implicated in cytoskeletal reorganization and subsequent morphological changes in various cell types. Among them, Rac and Cdc42 have been shown to be involved in neurite outgrowth in neuronal cells. In this study, we examined the role of RhoG, another member of Rho family GTPases, in nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Expression of wild-type RhoG in PC12 cells induced neurite outgrowth in the absence of NGF, and the morphology of wild-type RhoG-expressing cells was similar to that of NGF-differentiated cells. Constitutively active RhoG-transfected cells extended short neurites but developed large lamellipodial or filopodial structures at the tips of neurites. RhoG-induced neurite outgrowth was inhibited by coexpression with dominant-negative Rac1 or Cdc42. In addition, expression of constitutively active RhoG elevated endogenous Rac1 and Cdc42 activities. We also found that the NGF-induced neurite outgrowth was enhanced by expression of wild-type RhoG whereas expression of dominant-negative RhoG suppressed the neurite outgrowth. Furthermore, constitutively active Ras-induced neurite outgrowth was also suppressed by dominant-negative RhoG. Taken together, these results suggest that RhoG is a key regulator in NGF-induced neurite outgrowth, acting downstream of Ras and upstream of Rac1 and Cdc42 in PC12 cells.

DOI： 10.1128/mcb.20.19.7378-7387.2000

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DOI： 10.1046/j.1471-4159.2000.0750708.x

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DOI： 10.1016/s0014-5793(00)01508-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PORTLAND PRESS  

We reported recently that the activation of RhoA induced an increase in transepithelial electrical resistance (TER). To clarify effecters of Rho for this RhoA-induced regulation of tight-junction permeability, we introduced two effector-loop mutants of constitutively active RhoA(V14), RhoA(V14/L40) and RhoA(V14/C42), into Mardin-Darby canine kidney cells in an isopropyl beta-D-thiogalactoside-inducible expression system. RhoA(V14) and the two effector-loop mutants interacted in vitro with the Rho-binding domain of Rho-associated kinase, ROK alpha. Next we examined two parameters of Rho functions, stress-fibre formation and TER elevation, induced by RhoA(V14). Stress-fibre formation was induced by RhoA(V14/C42) but not by RhoA(V14/L40) On the other hand, TER elevation was induced by neither RhoA(V14/L40) nor RhoA(V14/C42). RhoA-associated kinase inhibitor, Y-27632, inhibited both stress-fibre formation and TER elevation induced by RhoA(V14). These results demonstrated that RhoA induced regulation of tight-junction permeability is mediated by Rho-associated kinase and at least one other unidentified effector, the coupling to RhoA being disrupted by mutation at position 40 or 42 in the effector loop.

DOI： 10.1042/0264-6021:3460617

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We reported previously that activation of the prostaglandin E receptor EP3 subtype triggered neurite retraction through the small GTPase Rho-, and its target, RhoA-binding kinase alpha. (ROKx)-, dependent pathway in EP3 receptor-expressing PC12 cells. Here we examined the involvement of tyrosine kinases in this pathway in nerve growth factor-differentiate PC12 cells. Tyrphostin; A25, a tyrosine kinase inhibitor, blocked neurite retraction and cell rounding induced by activation of the EP3 receptor, however, it failed to block neurite retraction and cell rounding induced by microinjection of constitutively active RhoA, RhoA(v14), indicating that a tyrphostin-sensitive tyrosine kinase was involved in the pathway from the EP3 receptor to Rho activation. On the other hand, genistein, another tyrosine kinase inhibitor, blocked neurite retraction and cell rounding induced by both activation of the EP3 receptor and microinjection of RhoA(v14). However, genistein did not block neuronal morphological changes induced by microinjection of a constitutively active mutant of ROK alpha. These results indicate that two different tyrosine kinases, tyrphostin A25-sensitive and genistein-sensitive kinases, are involved in the EP3 receptor-mediated neurite retraction acting upstream and downstream of Rho, respectively.

DOI： 10.1042/0264-6021:3400365

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DOI： 10.1074/jbc.273.44.28700

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(株)医薬ジャーナル社  

＜文献概要＞概日リズムにより,生体は地球の自転による明暗変動を予測し,最適に行動や代謝を調節することで生存率を向上させている。脳の視交叉上核(SCN)は,神経結合によって強固な振動体を形成し,概日リズムの最高位中枢として全身の細胞振動を統括している。ところが,明暗リズムが急激に変動する時差環境下では,SCNの概日振動がいったん停止し,時差ボケ状態となることが分かってきた。本稿では,時差症状を示さないマウスを用いて見出した時差環境下での再同調機構を紹介する。また,時差の社会問題として,慢性的な時差勤務によるシフトワーカーの生活習慣病リスクがあるが,その対処法についても考察したい。

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Language：English   Publisher：生命科学系学会合同年次大会運営事務局  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Language：English   Publisher：(公社)日本生化学会  

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概日リズムは、地球の自転によって従属的に形成されるものではなく、視床下部の視交叉上核(SCN)が自律的に駆動するものである。SCNのみを生体より取り出して切片培養条件下にし、SCN外からの入力を遮断した場合であっても、SCNは何ヵ月にもわたって概日リズムを示す。このリズム頑強性がSCNの中枢時計たる所以である。環境の明暗時計時間を変動させる時差実験により概日リズムを破綻させることで、概日リズムの頑強性を担う分子神経機構の解明を試み、その結果について述べた。

DOI： 10.1248/YAKUSHI.15-00206

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時差は,体内時計が容易に海外の現地時間にリセットされず,両者が不一致となるために起こる。今回,この不一致の神経生理機構とそれを裏打ちする分子機構が明らかとなった。驚くべきことに,時差では体内時計の中枢である視交叉上核の時計が止まり,これが回復するとともに時差が解消された。同時に,時差の分子機構の中枢を担っているのがバソプレッシンおよびそのV1a受容体とV1b受容体であることが解明され,その拮抗薬が時差解消に効果があった。時差は,近年急増するシフトワークによる生活習慣病の病因としても注目され,今後の展開が期待される。(著者抄録)

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睡眠覚醒や血圧など様々な生理機能に概日リズムが認められるが、それらは全て、視床下部にある視交叉上核(Suprachiasmatic Nucleus:SCN)により形成される。SCNの時刻シグナルは、神経伝達やホルモン等の液性因子を介して、数十兆個にもおよぶ全身の個々の末梢臓器に伝達され、そこで発振する末梢時計を調律する。最近、我々はSCNの分子時間生物学研究から、時差症状を示さないマウスの開発に成功した。本稿においては、時差の体内機構を中枢・末梢臓器の時間ネットワークの観点から述べる。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2012270757

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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