The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration

Tosini, Gianluca; Menaker, Michael

doi:10.1016/s0006-8993(97)01446-7

Cited by 201 publications

(172 citation statements)

References 29 publications

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“…These results also demonstrate that inner retinal circadian molecular rhythms persist in the absence of melatonin rhythms because rd mouse retinas exhibit low, arrhythmic melatonin levels (5). Because a few cones may have remained in the rd retinas we tested (32-34), we cannot rigorously conclude, based on this experiment alone, that the observed PER2 expression rhythms were completely endogenous to the inner nuclear and ganglion cell layers.…”

Section: Circadian Clocks In the Inner Nuclear And Ganglion Cell Layersmentioning

confidence: 84%

“…We used retinas from mPer2 Luc mice that were homozygous for rd and were 85 Ϯ 2 days old. At this age, virtually all photoreceptors have degenerated in the retinas of mice homozygous for rd (5,(32)(33)(34). Retinas were explanted onto membranes, and luminescence from the PER2::LUC fusion protein was continuously measured in real-time in constant darkness at 36.8°C.…”

Section: Coordinate Expression Of Core Clock Genes Occurs Preferentiamentioning

confidence: 99%

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Circadian organization of the mammalian retina

Ruan

Zhang

Zhou

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

148

181

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The mammalian retina contains an endogenous circadian pacemaker that broadly regulates retinal physiology and function, yet the cellular origin and organization of the mammalian retinal circadian clock remains unclear. Circadian clock neurons generate daily rhythms via cell-autonomous autoregulatory clock gene networks, and, thus, to localize circadian clock neurons within the mammalian retina, we have studied the cell type-specific expression of six core circadian clock genes in individual, identified mouse retinal neurons, as well as characterized the clock gene expression rhythms in photoreceptor degenerate rd mouse retinas. Individual photoreceptors, horizontal, bipolar, dopaminergic (DA) amacrines, catecholaminergic (CA) amacrines, and ganglion neurons were identified either by morphology or by a tyrosine hydroxylase (TH) promoter-driven red fluorescent protein (RFP) fluorescent reporter. Cells were collected, and their transcriptomes were subjected to multiplex single-cell RT-PCR for the core clock genes Period (Per) 1 and 2, Cryptochrome (Cry) 1 and 2, Clock, and Bmal1. Individual horizontal, bipolar, DA, CA, and ganglion neurons, but not photoreceptors, were found to coordinately express all six core clock genes, with the lowest proportion of putative clock cells in photoreceptors (0%) and the highest proportion in DA neurons (30%). In addition, clock gene rhythms were found to persist for >25 days in isolated, cultured rd mouse retinas in which photoreceptors had degenerated. Our results indicate that multiple types of retinal neurons are potential circadian clock neurons that express key elements of the circadian autoregulatory gene network and that the inner nuclear and ganglion cell layers of the mammalian retina contain functionally autonomous circadian clocks.circadian clock ͉ clock gene ͉ mouse retina ͉ photoreceptor ͉ real-time PCR T he mammalian retinal circadian clock exerts extensive control over retinal physiology and function, regulating a wide variety of retinal circadian rhythms, including rod disk shedding (1-3), melatonin release (4-6), dopamine synthesis (7, 8), electroretinogram (ERG) b-wave amplitude (9), extracellular pH (10), visual sensitivity (11, 12), and intraocular pressure (13,14). The retinal circadian clock and its dopamine-and melatonin-signaling molecules also influence pathological processes in the eye, including the susceptibility of photoreceptors to degeneration from light damage (15, 16), photoreceptor survival in animal models of retinal degeneration (17), and the degree of refractive errors in primate models of myopia (18). Despite its widespread influence, the cellular origin and organization of the circadian clock in the mammalian retina remain unclear.Neural circadian clocks generate endogenous circadian rhythms through cell-autonomous autoregulatory transcriptiontranslation feedback loops comprised of a defined set of ''clock genes'' in subsets of circadian pacemaker neurons. Gene targeting has demonstrated that, in mammals, the genes Period (Per) 1 and 2 and Cr...

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Section: Circadian Clocks In the Inner Nuclear And Ganglion Cell Layersmentioning

confidence: 84%

Section: Coordinate Expression Of Core Clock Genes Occurs Preferentiamentioning

confidence: 99%

Circadian organization of the mammalian retina

Ruan

Zhang

Zhou

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

148

181

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“…In vivo experiments have suggested the presence of yet another circadian oscillator in the chicken retina that would control local melatonin production [43]; however, in vitro experiments confirming this point are still needed. The existence of a retinal clock controlling melatonin production has been demonstrated in vitro for Xenopus [6,10], zebrafish [9], hamster [39] and mouse [40]. Day/night changes in mRNA levels have been observed, in both the pineal gland and the retina, for three of the enzymes of the melatonin biosynthesis pathway: tryptophan hydroxylase (TPH, E.C.1.14.16.4), which converts tryptophan to 5-hydroxytryptophan, arylalkylamine-N-acetyltransferase (AANAT, E.C.2.3.1.87), which converts 5-hydroxytryptamine (serotonin) to N-acetyl-5-hydroxytryptamine (N-acetylserotonin) and hydroxyindole-O-methyltransferase (HIOMT, E.C.2.1.1.4), which converts N-acetylserotonin to melatonin.…”

Section: Introductionmentioning

confidence: 99%

Melatonin synthesis pathway: circadian regulation of the genes encoding the key enzymes in the chicken pineal gland and retina

Bernard¹,

Guerlotté²,

Grève³

et al. 1999

Reprod. Nutr. Dev.

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-The mRNAs encoding three enzymes of the melatonin synthesis pathway (tryptophan hydroxylase (TPH), arylalkylamine-N-acetyltransferase (AANAT) and hydroxyindole-O-methyltransferase (HIOMT)) are expressed with a day/night rhythm in the chicken pineal gland and retina. TPH and AANAT mRNA levels reach their peak at night. HIOMT mRNA levels peak at night in the retina, but during the day in the pineal gland. In this tissue, the rhythm of TPH, AANAT and HIOMT mRNA levels persisted in constant darkness (DD), both in vivo and in vitro, indicating that the three genes are controlled by the circadian oscillator of the chicken pineal. In the retina, the rhythms of TPH and AANAT mRNA levels also persisted in DD in vivo, suggesting that they are driven by a circadian oscillator. In contrast, the rhythm of HIOMT mRNA in the retina appeared to be controlled only by light. The clones of chicken AANAT and HIOMT genes that we have isolated should help us to understand the molecular mechanisms of: 1) their transcriptional regulation by circadian oscillators and by light; 2) their tissue-specific expression in the pineal gland and the retina. © Inra/ Elsevier,

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“…Similarly, a circadian clock is located in Xenopus retinal photoreceptor cells (8,18,19) and pike and zebrafish pinealocytes (20 -22) where it regulates rhythmic synthesis of melatonin. Recent in vitro experiments have also demonstrated that these clock properties exist in mammalian retina (23,24).…”

mentioning

confidence: 96%

Characterization of the Chicken SerotoninN-Acetyltransferase Gene

Chong¹,

Bernard²,

Klein

2000

Journal of Biological Chemistry

131

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The abundance of serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) mRNA in the chicken pineal gland exhibits a circadian rhythm, which is translated into a circadian rhythm in melatonin production. Here we have started to elucidate the molecular basis of the circadian rhythm in chicken AANAT (cAANAT). The 5-flanking region of the cAANAT gene was isolated and found to contain an E box DNA element that confers strong luciferase reporter activity. In transfection experiments using chicken pineal cells, an E box mutation dramatically decreased reporter activity. Northern blot analysis indicated that several putative clock genes (bmal1, Clock, and MOP4) are co-expressed in the chicken pineal gland. bmal1 mRNA is expressed in a rhythmic manner in the chicken pineal gland, with peak levels at early subjective night, coincident with the increase in cAANAT expression. Co-transfection experiments in COS cells demonstrated that chicken BMAL1/ CLOCK and human BMAL1/MOP4 heterodimers bound the AANAT E box element and enhanced transcription. These observations suggest that binding of clock gene heterodimers to the cAANAT E box is a critical element in the expression of the cAANAT gene in vitro.

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The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration

Cited by 201 publications

References 29 publications

Circadian organization of the mammalian retina

Circadian organization of the mammalian retina

Melatonin synthesis pathway: circadian regulation of the genes encoding the key enzymes in the chicken pineal gland and retina

Characterization of the Chicken SerotoninN-Acetyltransferase Gene

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