scholarly journals RNA Splicing Factor Mutations That Cause Retinitis Pigmentosa Result in Circadian Dysregulation

2019 ◽  
Vol 35 (1) ◽  
pp. 72-83
Author(s):  
Iryna Shakhmantsir ◽  
Scott J. Dooley ◽  
Siddharth Kishore ◽  
Dechun Chen ◽  
Eric Pierce ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Rna Splicing ◽  
Wheel Running ◽  
Activity Rhythm ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Splicing Factor ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Period Lengthening

Circadian clocks regulate multiple physiological processes in the eye, but their requirement for retinal health remains unclear. We previously showed that Drosophila homologs of spliceosome proteins implicated in human retinitis pigmentosa (RP), the most common genetically inherited cause of blindness, have a role in the brain circadian clock. In this study, we report circadian phenotypes in murine models of RP. We found that mice carrying a homozygous H2309P mutation in Pre-mRNA splicing factor 8 ( Prpf8) display a lengthened period of the circadian wheel-running activity rhythm. We show also that the daily cycling of circadian gene expression is dampened in the retina of Prpf8-H2309P mice. Surprisingly, molecular rhythms are intact in the eye cup, which includes the retinal pigment epithelium (RPE), even though the RPE is thought to be the primary tissue affected in this form of RP. Downregulation of Prp31, another RNA splicing factor implicated in RP, leads to period lengthening in a human cell culture model. The period of circadian bioluminescence in primary fibroblasts of human RP patients is not significantly altered. Together, these studies link a prominent retinal disorder to circadian deficits, which could contribute to disease pathology.

Activity rhythm of golden hamster (Mesocricetus auratus) can be entrained to a 19-h light-dark cycle

2005 ◽  
Vol 289 (4) ◽  
pp. R998-R1005 ◽  
Author(s):  
Juan J. Chiesa ◽  
Montserrat Anglès-Pujolràs ◽  
Antoni Díez-Noguera ◽  
Trinitat Cambras
Keyword(s):  
Golden Hamster ◽  
Wheel Running ◽  
Activity Rhythm ◽  
Mesocricetus Auratus ◽  
Precise Determination ◽  
Dark Cycle ◽  
Running Wheel ◽  
Running Activity ◽  
Wheel Running Activity

Both temporary access to a running wheel and temporary exposure to light systematically influence the phase producing entrainment of the circadian activity rhythm in the golden hamster ( Mesocricetus auratus). However, precise determination of entrainment limits remains methodologically difficult, because such calculations may be influenced by varying experimental paradigms. In this study, effects on the entrainment of the activity pattern during successive light-dark (LD) cycles of stepwise decreasing periods, as well as wheel running activity, were investigated. In particular, the hamster activity rhythm under LD cycles with a period (T) shorter than 22 h was studied, i.e., when the LD cycle itself had been shown to be an insufficiently strong zeitgeber to synchronize activity rhythms. Indeed, it was confirmed that animals without a wheel do not entrain under 11:11-h LD cycles (T = 22 h). Subsequently providing hamsters continuous access to a running wheel established entrainment to T = 22 h. Moreover, this paradigm underwent further reductions of the T period to T = 19.6 h without loss of entrainment. Furthermore, restricting access to the wheel did not result in loss of entrainment, while even entrainment to T = 19 h was observed. To explain this observed shift in the lower entrainment limit, our speculation centers on changes in pacemaker response facilitated by stepwise changes of T spaced very far apart, thus allowing time for adaptation.

scholarly journals Age-related changes in circadian responses to dark pulses

2000 ◽  
Vol 279 (2) ◽  
pp. R586-R590 ◽  
Author(s):  
Marilyn J. Duncan ◽  
Anthony W. Deveraux
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Circadian Pacemaker ◽  
Running Activity ◽  
Age Related ◽  
Wheel Running Activity ◽  
Significant Difference ◽  
Time Signals ◽  
Dark Pulse ◽  
Age Related Changes

Aging involves many alterations in circadian rhythms, including a loss of sensitivity to both photic and nonphotic time signals. This study investigated the sensitivity of young and old hamsters to the phase advancing effect of a 6-h dark pulse on the locomotor activity rhythm. Each hamster was tested four times during a period of ∼9 mo; periods of exposure to a 14-h photoperiod were alternated with the periods of exposure to constant light (20–80 lx), during which the dark pulses were administered. There was no significant difference in the phase shifts exhibited by the young (4–10 mo) and old hamsters (19–25 mo) or in the amount of wheel running activity displayed during each dark pulse. However, young hamsters had a significantly greater propensity to exhibit split rhythms immediately after the dark pulses. These results suggest that, although aging does not reduce the sensitivity of the circadian pacemaker to this nonphotic signal, it alters one property of the pacemaker, i.e., the flexibility of the coupling of its component oscillators.

Failure of pinealectomy or melatonin to alter circadian activity rhythm of the rat

1982 ◽  
Vol 242 (3) ◽  
pp. R261-R264 ◽  
Author(s):  
P. W. Cheung ◽  
C. E. McCormack
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Physiological Mechanism ◽  
Continuous Darkness ◽  
Running Activity ◽  
Melatonin Administration ◽  
Wheel Running Activity ◽  
Free Running ◽  
Dim Light ◽  
Free Running Period

These experiments were undertaken to determine if the pineal gland is involved in the physiological mechanism by which the rat alters its free-running period (tau) in response to changes in illuminance. Spontaneous wheel-running activity was recorded from pinealectomized or sham-operated female Charles River rats. The tau of running activity was determined in continuous darkness (DD) or in continuous dim light (LL). Pinealectomized rats and sham-operated rats lengthened their tau's to approximately the same extent when shifted from DD to LL and shortened their tau's when shifted back to DD. Continuous melatonin administration via Silastic capsules failed to alter tau of rats kept in dim LL. These results indicate that the pineal is not primarily involved in the mechanism by which the rat alters tau in response to changes in illuminance.

Aging and photoperiod affect entrainment and quantitative aspects of locomotor behavior in Syrian hamsters

1997 ◽  
Vol 272 (4) ◽  
pp. R1219-R1225 ◽  
Author(s):  
K. Scarbrough ◽  
S. Losee-Olson ◽  
E. P. Wallen ◽  
F. W. Turek
Keyword(s):  
Locomotor Activity ◽  
Wheel Running ◽  
Activity Rhythm ◽  
Age Groups ◽  
Temporal Distribution ◽  
Similar Rate ◽  
Middle Aged ◽  
Running Activity ◽  
Age Related ◽  
Wheel Running Activity

Aging affects the regulation of diurnal and circadian rhythmicity. We tested the hypothesis that the age-related difference in the phase angle of entrainment of the locomotor activity rhythm to a light-dark (LD) cycle would be greater under LD 6:18 than LD 14:10. We also analyzed changes in quantitative aspects of wheel-running behavior according to age group. Young (9-wk-old), middle-aged (11- to 12-mo-old), and old (15- to 17-mo-old) male golden hamsters were entrained to a 14:10 LD cycle followed by re-entrainment to a 6:18 LD cycle. Fourteen days after the start of locomotor recording in LD 14:10 and again after 27 days in LD 6:18, the phase of activity onset, the total number of wheel revolutions performed per day, the peak intensity of wheel-running activity, the duration of the active period, and the level of fragmentation of locomotor activity were quantitated. We also studied the temporal distribution of the largest bout of wheel-running activity among the age groups in both photoperiods. Short days induced testicular regression at a similar rate among young, middle-aged, and old hamsters. The data are discussed in terms of the effects of age on overall circadian organization in the seasonally changing environment.

Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice

1997 ◽  
Vol 273 (6) ◽  
pp. R1957-R1964 ◽  
Author(s):  
Verónica S. Valentinuzzi ◽  
Kathryn Scarbrough ◽  
Joseph S. Takahashi ◽  
Fred W. Turek
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Laboratory Mouse ◽  
Active Phase ◽  
Constant Darkness ◽  
Age Difference ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Activity Onset ◽  
Old Mice

The effects of age on the circadian clock system have been extensively studied, mainly in two rodent species, the laboratory rat and the golden hamster. However, less information is available on how aging alters circadian rhythmicity in a commonly studied rodent animal model, the mouse. Therefore, in the present study we compared the rhythm of wheel-running activity in adult (6–9 mo) and old (19–22 mo) C57BL/6J mice maintained under different lighting conditions for a period of 4 mo. During this period, mice were subjected to phase advances and phase delays of the light-dark (LD) cycle and eventually to constant darkness (DD). In LD (12 h light, 12 h dark), old mice exhibited delayed activity onset relative to light offset and an increase in the variability of activity onset compared with adult mice. After a 4-h phase advance of the LD cycle, old mice took significantly longer to reentrain their activity rhythm when compared with adult animals. Old mice also demonstrated a decline in the number of wheel revolutions per day and a tendency toward a decrease in the length of the active phase. An increase in fragmentation of activity across the 24-h day was obvious in aging animals, with bouts of activity being shorter and longer rest periods intervening between them. No age difference was detected in the maximum intensity of wheel-running activity. In DD, the free-running period was significantly longer in old mice compared with adults. In view of the rapidly expanding importance of the laboratory mouse for molecular and genetic studies of the mammalian nervous system, the present results provide a basis at the phenotypic level to begin to apply genetic methods to the analysis of circadian rhythms and aging in mammals.

Melatonin and activity rhythm responses to light pulses in mice with the Clock mutation

2003 ◽  
Vol 284 (5) ◽  
pp. R1231-R1240 ◽  
Author(s):  
David J. Kennaway ◽  
Athena Voultsios ◽  
Tamara J. Varcoe ◽  
Robert W. Moyer
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Mutant Mice ◽  
Constant Darkness ◽  
Wild Type ◽  
Continuous Darkness ◽  
Light Pulses ◽  
Essentially Normal ◽  
Running Activity ◽  
Wheel Running Activity

Melatonin and wheel-running rhythmicity and the effects of acute and chronic light pulses on these rhythms were studied in Clock Δ19 mutant mice selectively bred to synthesize melatonin. Homozygous melatonin-proficient Clock Δ19 mutant mice ( Clock Δ19/Δ19 -MEL) produced melatonin rhythmically, with peak production 2 h later than the wild-type controls (i.e., just before lights on). By contrast, the time of onset of wheel-running activity occurred within a 20-min period around lights off, irrespective of the genotype. Melatonin production in the mutants spontaneously decreased within 1 h of the expected time of lights on. On placement of the mice in continuous darkness, the melatonin rhythm persisted, and the peak occurred 2 h later in each cycle over the first two cycles, consistent with the endogenous period of the mutant. This contrasted with the onset of wheel-running activity, which did not shift for several days in constant darkness. A light pulse around the time of expected lights on followed by constant darkness reduced the expected 2-h delay of the melatonin peak of the mutants to ∼1 h and advanced the time of the melatonin peak in the wild-type mice. When the Clock Δ19/Δ19 -MEL mice were maintained in a skeleton photoperiod of daily 15-min light pulses, a higher proportion entrained to the schedule (57%) than melatonin-deficient mutants (9%). These results provide compelling evidence that mice with the Clock Δ19 mutation express essentially normal rhythmicity, albeit with an underlying endogenous period of 26–27 h, and they can be entrained by brief exposure to light. They also raise important questions about the role of Clock in rhythmicity and the usefulness of monitoring behavioral rhythms compared with hormonal rhythms.

scholarly journals Pre-mRNA Processing Factors and Retinitis Pigmentosa: RNA Splicing and Beyond

2021 ◽  
Vol 9 ◽  
Author(s):  
Chunbo Yang ◽  
Maria Georgiou ◽  
Robert Atkinson ◽  
Joseph Collin ◽  
Jumana Al-Aama ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Rna Splicing ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Mrna Processing ◽  
Retinal Cell ◽  
Current Evidence ◽  
Patient Specific ◽  
Human Patient ◽  
Processing Factors

Retinitis pigmentosa (RP) is the most common inherited retinal disease characterized by progressive degeneration of photoreceptors and/or retinal pigment epithelium that eventually results in blindness. Mutations in pre-mRNA processing factors (PRPF3, 4, 6, 8, 31, SNRNP200, and RP9) have been linked to 15–20% of autosomal dominant RP (adRP) cases. Current evidence indicates that PRPF mutations cause retinal specific global spliceosome dysregulation, leading to mis-splicing of numerous genes that are involved in a variety of retina-specific functions and/or general biological processes, including phototransduction, retinol metabolism, photoreceptor disk morphogenesis, retinal cell polarity, ciliogenesis, cytoskeleton and tight junction organization, waste disposal, inflammation, and apoptosis. Importantly, additional PRPF functions beyond RNA splicing have been documented recently, suggesting a more complex mechanism underlying PRPF-RPs driven disease pathogenesis. The current review focuses on the key RP-PRPF genes, depicting the current understanding of their roles in RNA splicing, impact of their mutations on retinal cell’s transcriptome and phenome, discussed in the context of model species including yeast, zebrafish, and mice. Importantly, information on PRPF functions beyond RNA splicing are discussed, aiming at a holistic investigation of PRPF-RP pathogenesis. Finally, work performed in human patient-specific lab models and developing gene and cell-based replacement therapies for the treatment of PRPF-RPs are thoroughly discussed to allow the reader to get a deeper understanding of the disease mechanisms, which we believe will facilitate the establishment of novel and better therapeutic strategies for PRPF-RP patients.

scholarly journals USH2A-Related Retinitis Pigmentosa: Staging of Disease Severity and Morpho-Functional Studies

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 213
Author(s):  
Benedetto Falsini ◽  
Giorgio Placidi ◽  
Elisa De Siena ◽  
Maria Cristina Savastano ◽  
Angelo Maria Minnella ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Usher Syndrome ◽  
Collaborative Study ◽  
Staging System ◽  
International Standards ◽  
Full Field ◽  
Functional Studies ◽  
Cumulative Score

Usher syndrome type 2A (USH2A) is a genetic disease characterized by bilateral neuro-sensory hypoacusia and retinitis pigmentosa (RP). While several methods, including electroretinogram (ERG), describe retinal function in USH2A patients, structural alterations can be assessed by optical coherence tomography (OCT). According to a recent collaborative study, RP can be staged considering visual acuity, visual field area and ellipsoid zone (EZ) width. The aim of this study was to retrospectively determine RP stage in a cohort of patients with USH2A gene variants and to correlate the results with age, as well as additional functional and morphological parameters. In 26 patients with established USH2A genotype, RP was staged according to recent international standards. The cumulative staging score was correlated with patients’ age, amplitude of full-field and focal flicker ERGs, and the OCT-measured area of sub-Retinal Pigment Epithelium (RPE) illumination (SRI). RP cumulative score (CS) was positively correlated (r = 0.6) with age. CS was also negatively correlated (rho = −0.7) with log10 ERG amplitudes and positively correlated (r = 0.5) with SRI. In USH2A patients, RP severity score is correlated with age and additional morpho-functional parameters not included in the international staging system and can reliably predict their abnormality at different stages of disease.

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