Malcolm von Schantz | University of Surrey (original) (raw)

Papers by Malcolm von Schantz

Brain Research, 1997

The Syrian golden hamster (Mesocricetus auratus) is an important model in the study of circadian ... more The Syrian golden hamster (Mesocricetus auratus) is an important model in the study of circadian rhythms. However, as in other mammals, little is known about the photoreceptors that mediate circadian entrainment. Using immunocytochemistry and RNA blot hybridization, we found no evidence for the presence of blue-/UV-sensitive opsin. In contrast, green-sensitive cone opsin was demonstrated in the retina both by immunocytochemistry and reverse-transcription PCR. When used as a probe in RNA blot hybridization, this PCR fragment labelled one transcript (5.8 kb) in hamster retinal RNA. These findings are in accordance with preliminary data from other investigators using electroretinography, which showed one cone-mediated photoreceptive mechanism with a maximum sensitivity of 501 nm, but none at shorter wavelengths. However, we found that non-saturating pulses of ultraviolet radiation (357 nm) caused phase shifts in locomotor behaviour. These results corroborate earlier reports that UV radiation can regulate the photoperiodic response in this animal. Having confirmed these apparently contradictory earlier reports, we discuss the mechanisms that might create a UV-triggered non-visual response in a green cone monochromat. Finally, we propose the use of the Syrian golden hamster as a model for photoreceptor development and function in the absence of S/UV cones.

O ur perception of the world is so dominated by our sense of vision that we have been reluctant t... more O ur perception of the world is so dominated by our sense of vision that we have been reluctant to accept the fact that the vertebrate eye mediates another, quite separate photosensory task-the detection of light for the regulation of biological time. In this short article, we outline some of the recent experimental findings that show that the absence of rod and cone photoreceptors does not block the effects of light on the circadian system. Furthermore, we review the progress to date in identifying the photopigments that may mediate the effects of light on the mammalian biological clock.

Journal of Insect Physiology, 1999

In an attempt to identify the brain photoreceptors that mediate the photoperiodic response of the... more In an attempt to identify the brain photoreceptors that mediate the photoperiodic response of the vetch aphid, Megoura viciae, we utilised immunocytochemical techniques and employed 20 antibodies directed against invertebrate and vertebrate opsins and phototransduction proteins. A sub-set of these antibodies (to Drosophila rhodopsin 1: RH1-1; vertebrate cone opsins: COS-1; CERN-874; CERN-933; vertebrate rod opsin: CERN-901; vertebrate arrestin: AB-Arr; vertebrate transducin+arrestin+rhodopsin kinase+cGMP phosphodiesterase: CERN-911; and vertebrate cellular retinoid binding protein: CRALBP) consistently labelled an anterior ventral neuropile region of the protocerebrum. These anatomical findings, coupled with previous localised illumination and micro-lesion studies, provide strong evidence that this region of the aphid brain houses the photoperiodic photoreceptors. The present study also confirms that the medial (Group I) neurosecretory cells are not the photoperiodic photoreceptors.

Journal of Biological Rhythms, 2005

Period homologue 3 (PER3) is a component of the mammalian circadian system, although its precise ... more Period homologue 3 (PER3) is a component of the mammalian circadian system, although its precise role is unknown. A biallelic variable number tandem repeat (VNTR) polymorphism exists in human PER3, consisting of 4 or 5 repeats of a 54-bp sequence in a region encoding a putative phosphorylation domain. This polymorphism has previously been reported to associate with diurnal preference ("morningness" and "eveningness") and delayed sleepphase syndrome. We have investigated the global allele frequencies of this variant in ethnically distinct indigenous populations. All populations were polymorphic, with the shorter (4-repeat) allele ranging in frequency from 0.19 (Papua New Guinea) to 0.89 (Mongolia). To investigate if allele frequency has been influenced by natural selection, the authors 1) tested for a correlation with latitude and mean annual insolation (incident sunlight energy), using classical markers to correct for historical population differentiation; and they 2) compared allelefrequency difference between European American, African American, and East Asian populations, as measured using F ST , to an empirical null distribution of F ST values based on a genome-wide dataset of single nucleotide polymorphisms (SNPs) of presumed neutral loci that were previously typed by The SNP Consortium. The variation in allele frequencies between indigenous populations did not show a pattern that would indicate selective pressure on PER3 resulting from day-length variation or mean annual insolation, and the allele-frequency difference between European Americans, African Americans, and East Asians was not an outlier when compared to the distribution for presumed neutral SNPs. We therefore find no evidence for differential or balancing selection in the contemporary pattern of global PER3 allele frequencies.

Journal of The Royal Society of Medicine, 2003

Do but consider what an excellent thing sleep is; it is so inestimable a jewel that, if a tyrant ... more Do but consider what an excellent thing sleep is; it is so inestimable a jewel that, if a tyrant would give his crown for an hour's slumber, it cannot be bought; of so beautiful a shape is it, that though a man lie with an Empress, his heart cannot beat quiet till he leaves her embracements to be at rest with the other: yea, so greatly indebted are we to this kinsman of death, that we owe the better tributary, half of our life to him: and there is good cause why we should do so: for sleep is that golden chain that ties health and our bodies together.-Thomas Dekker (The Gull's Hornbook, 1609) Circadian rhythms are endogenously generated rhythms that approximate the length of a day and a night. They are found in most organisms whose life span is counted in days or greater units, rather than hours. 1 They enable the organism to anticipate, rather than passively adjust to, the changes imposed by alternation between day and night. These changes relate to positive functions such as vision and negative effects such as ultraviolet light damage. They also include indirectly generated alternations such as temperature, availability of food and prevalence of predators.

Journal of Sleep Research, 2002

Mutations in clock genes are associated with abnormal circadian parameters, including sleep. An a... more Mutations in clock genes are associated with abnormal circadian parameters, including sleep. An association has been reported previously between a polymorphism (3111C), situated in the 3′-untranslated region (3′-UTR) of the circadian gene Clock and evening preference. In the present study, this polymorphism was assessed in: (1) 105 control subjects with defined diurnal preference, (2) 26 blind subjects with free-running circadian rhythms and characterized with regard to circadian period (τ) and (3) 16 delayed sleep phase syndrome patients. The control group was chosen from a larger population (n = 484) by Horne-Östberg questionnaire analysis, from which three subgroups were selected (evening, intermediate and morning preference). Data from sleep diaries completed by 90% of these subjects showed a strong correlation between preferred and estimated timings of sleep and wake. The mean timings of activities for the evening group were at least 2 h later than the morning group. Genetic analysis showed that, in contrast with the previously published finding, there was no association between 3111C and eveningness. Neither was there an association between 3111C and τ, nor a significant difference in 3111C frequency between the normal and delayed sleep phase syndrome groups. To assess the effect of this polymorphism on messenger RNA (mRNA) translatability, luciferase reporter gene constructs containing the two Clock polymorphic variants in their 3′-UTR were transfected into COS-1 cells and luciferase activity measured. No significant difference was observed between the two variants. These results do not support Clock 3111C as a marker for diurnal preference, τ, or delayed sleep phase syndrome in humans.

Chronobiology International, 2009

Although there are significant intra-individual differences in self-reported diurnal preference, ... more Although there are significant intra-individual differences in self-reported diurnal preference, as measured by validated questionnaires, the relative contribution of exogenous and endogenous factors to self-reported diurnal preference largely remains to be investigated. The present study examined which items from the Horne-Ostberg (HO) questionnaire of diurnal preference were better at predicting genotypes in the variable number tandem polymorphism (VNTR) in the coding region of the gene PER3. This polymorphism has previously been reported to associate with diurnal preference, sleep parameters, and cognitive performance markers following sleep deprivation. Participants (n=240, selected from a previously studied population) had completed the HO questionnaire and provided a DNA sample, which was genotyped with regard to the PER3 VNTR. A multinomial logistic regression showed that four items significantly increased prediction accuracy between the two homozygotic genotypes, with homozygotes for the longer variant of the gene (PER3(5/5)) associated with answers indicating a stronger morning preference than those chosen by homozygotes for the shorter variant (PER3(4/4)). Only one item, the question of whether the respondent required an alarm clock, discriminated between all three genotypes. Moreover, when the items were divided into those with the strongest versus the weakest genetic association, there was a significant relationship between age and the questions not predicting genotype, but not between age and genotype-predictive questions. This may explain previous findings regarding age-related differences in self-reported diurnal preference. These findings could facilitate the future development of diurnal preference scales especially tailored to the study of specific biological parameters.

Chronobiology International, 2007

The relationship between diurnal preference, as measured by the Horne-Ostberg questionnaire, and ... more The relationship between diurnal preference, as measured by the Horne-Ostberg questionnaire, and quantifiable personality traits was investigated in 617 participants. A hierarchical multiple regression analysis demonstrated that out of the personality variables, conscientiousness was the single biggest predictor of diurnal preference (beta=0.246), after controlling for depression, sleep disorders, shift work, age, gender, and demographic characteristics. Morningness has previously been associated with physiological parameters of the circadian clock and with polymorphisms in circadian clock genes, suggesting the possibility that conscientiousness, too, may be linked to the same parameters.

Journal of Human Genetics, 2006

The three PERIOD proteins form a major negative feedback component of the molecular mechanism gov... more The three PERIOD proteins form a major negative feedback component of the molecular mechanism governing the periodicity of the vertebrate circadian clock. Genetic variations within the human PER2 and PER3 genes have been linked with diurnal preference and disorders of sleep timing. We screened the coding region of PER1, as well as the 5′- and 3′-untranslated regions and the promoter region, for polymorphisms. The T2434C polymorphism in exon 18, a synonymous substitution, associated with extreme diurnal preference. The C allele was more frequent in subjects with extreme morning preference (frequency = 0.24) than in subjects with extreme evening preference (frequency = 0.12). No significant association was observed between either allele and delayed sleep phase syndrome. This polymorphism may have a direct effect on RNA translatability, or be in linkage disequilibrium with another polymorphism which affects PER1 expression at the DNA, RNA, or protein level. This is the first reported association between a PER1 polymorphism and extreme diurnal preference. Functionally important polymorphisms in PER1 are rare, which may indicate that it is subject to more stringent selection pressure than the other PER genes.

Molecular Brain Research, 1999

The mammalian retina contains an autonomous circadian oscillator that can sustain rhythms in oute... more The mammalian retina contains an autonomous circadian oscillator that can sustain rhythms in outer segment disc shedding and Ž . melatonin synthesis even in the absence of cues from the central oscillator in the suprachiasmatic nucleus SCN . The present investigation aimed to ascertain whether the steady-state levels of rod and cone opsin mRNA exhibited a circadian oscillation in the mouse, and if so, to characterise this oscillation with regard to phase. Retinas were collected from mice free-running in constant darkness Ž . at circadian times CT 0, 4, 12, 16, and 20. RNA was extracted for the production of Northern blots, which were sequentially hybridised Ž . with probes for a-tubulin control , ultraviolet opsin, and rhodopsin. Whereas no significant oscillation was detected in the levels of a-tubulin, the levels of both ultraviolet opsin and rhodopsin transcripts oscillated with an amplitude of at least 3-fold. The highest levels Ž . were found at around CT12 which corresponds to the subjective evening, the time of activity onset in the mouse . These results show that the levels of rod and cone photopigment mRNA are under circadian control. The significance of the rhythms and their phasing is discussed. These findings have potential clinical implications both with regard to nocturnal light treatment of phase asynchrony, and in the timing of chemo-and radiotherapy. q

Journal of Sleep Research, 2007

The objective of this study was to investigate the effect of age on the association between prefe... more The objective of this study was to investigate the effect of age on the association between preferred timing of sleep and waking activities and a coding-region variable number tandem repeat (VNTR) polymorphism in the clock gene PER3. We have previously reported this polymorphism to associate with diurnal preference and delayed sleep phase syndrome (DSPS). Participants (n = 1590; 707 males and 883 females) completed the Horne–Östberg (HÖ) questionnaire for diurnal preference and provided a DNA sample. Overall HÖ scores were plotted against age. The 5% extremes and intermediates were selected for genotyping. Frequencies of the PER3 4- and 5-repeat alleles were examined in separate age groups (18–29, 30–39, 40–49 and 50+ years of age). The 4-repeat allele was significantly more frequent in evening types, and the 5-repeat allele more frequent in morning types (Fisher's exact test, P = 0.016). Analysis in the four age groupings revealed that the strength of this association attenuated with age and was significant only in the youngest group (18–29 years). These results extend our previous finding of an association between the PER3 VNTR and diurnal preference. They also demonstrate that diurnal preference in young people is more closely associated with this polymorphism than it is in other age groups.

Journal of Biological Rhythms, 2005

Page 1. http://jbr.sagepub.com/ Journal of Biological Rhythms http://jbr.sagepub. com/content/20/... more Page 1. http://jbr.sagepub.com/ Journal of Biological Rhythms http://jbr.sagepub. com/content/20/5/470 The online version of this article can be found at: DOI: 10.1177/0748730405278442 2005 20: 470 J Biol Rhythms Aaron ...

Journal of Molecular Evolution, 2006

Circadian clock genes are remarkably conserved between eucoelomates. Although Drosophila has one ... more Circadian clock genes are remarkably conserved between eucoelomates. Although Drosophila has one copy of each major component, vertebrates have two or (in the case of the Period genes) three paralogs (Per1-3). We investigated the possibility that the vertebrate Per genes arose through two genome duplications during the emergence of vertebrates. Phylogenetic trees have placed zebrafish and mammalian Per1 and 2 together in a separate branch from Per3. The positions of four coding region splice sites were conserved between Drosophila per and the human paralogs, the fifth one being unique to Drosophila. The human PER genes shared the positions of all coding region splice sites, except the first two in PER1 and PER2 (which PER3 lacks). The phases of all splice sites were conserved between all four genes with two exceptions. Analysis of all genes within 10 Mb of the human PER1-3 genes, which are located 7.8—8.8 Mb from the telomeres on chromosomes 17, 2, and 1, identified several orthologous neighbors shared by at least two PER genes. Two gene families, HES (hairy and Enhancer of Split) and KIF1 (kinesin-like protein 1), were represented in all three of these paralogons. Although no functional fourth human PER paralog exists, five representatives from the same gene families were found close to the telomer of chromosome 3. We conclude that the ancestral chordate Per gene underwent two duplication events, giving rise to Per1—3 and a lost fourth paralog.

Purpose. This study describes the expression and distribution of phototransduction cascade gene p... more Purpose. This study describes the expression and distribution of phototransduction cascade gene products in the cone-dominant retina of the ground squirrel Spermophilus tridecemlineatus.

European Journal of Neuroscience, 2004

Macroarray analysis was used to compare equal amounts of cDNA from wild-type and rd/rd (retinal d... more Macroarray analysis was used to compare equal amounts of cDNA from wild-type and rd/rd (retinal degeneration) mice, collected at P90 when photoreceptor degeneration is virtually complete. A stronger signal for the glycolytic enzyme phosphoglucose isomerase (Gpi1) was observed in the rd/rd sample. Extracellularly, Gpi1 may act as a cytokine, independently described as neuroleukin and autocrine motility factor. Retinal Gpi1 expression was investigated by Northern and Western blot analysis and immunohistochemistry. Double-labelling was performed with antibodies against Gpi1 and calbindin-D, glutamine synthetase, RPE65, calretinin and ultraviolet opsin in order to provide positive cell type identi®cation. Northern and Western blots showed double expression levels per microgram of RNA and protein, respectively, in the rd/rd retina compared with wild-type. However, the total amount of Gpi1 protein per retina was indistinguishable. Gpi1 immunoreactivity was found in ganglion, amacrine, horizontal and bipolar cells, but not in rods, cones, pigment epithelium and Muller cells. This distribution explains why the absolute amounts of Gpi1 protein were not appreciably different between wild-type and the rd/rd phenotype, where rods and cones are absent, whilst the relative contribution of Gpi1 to the total protein and RNA pools differed. Some extracellular immunoreactivity was observed in the photoreceptor matrix around cones in freshly ®xed tissue only, which could possibly re¯ect a role as a cytokine. We propose that glycolysis in Gpi1-negative cells proceeds entirely through the pentose phosphate pathway, creating NADPH at the cost of organic carbon. We hypothesize that the unique metabolic needs of photoreceptors justify this trade-off.

Purpose. Peanut agglutinin lectin (PNA) is known for its selective binding to cone cells and to t... more Purpose. Peanut agglutinin lectin (PNA) is known for its selective binding to cone cells and to the cone domains of the interphotoreceptor matrix. In the current study, the authors investigated whether there is any difference in PNA binding between color-specific cones of the cone-dominant ground squirrel.

Molecular Brain Research, 1998

Recent evidence suggests that the two main classes of cones are not only equipped with different ... more Recent evidence suggests that the two main classes of cones are not only equipped with different photopigments, but also exhibit Ž . differences in their downstream phototransduction cascade. An antibody against the g subunit of retinal cGMP phosphodiesterase PDE Ž . had previously been found to label all photoreceptors in the ground squirrel Spermophilus tridecemlineatus . This property was utilized for the cloning of a cDNA fragment encoding the corresponding polypeptide. A lgt11 cDNA library was constructed and screened with the antibody. Positive clones were isolated, subcloned, and sequenced. Clones were used as probes in RNA blot hybridization, and the obtained sequence information was compared to other available g-PDE sequences. Four virtually identical cDNA clones were isolated. Both nucleic acid and amino acid sequence alignment placed this gene in the same group as bovine and human cone g-phosphodiesterase subunits. The predicted length of the translated protein was 84 amino acids, and its molecular weight 11 kD. The cDNA hybridized with an 0.6-kb transcript in retinal RNA from ground squirrel, Syrian golden hamster, and mouse, and also with a 1.4-kb transcript in the ground squirrel. We conclude that the isolated cDNA fragment encodes a g subunit of cone cGMP-PDE. This subunit is expressed in Ž . middle-wavelength sensitive cones the predominant photoreceptor type in this species . It remains to be determined if this subunit is expressed in short-wavelength sensitive cones as well, or if these photoreceptors are equipped with another, unique g-PDE subunit. q 1998 Elsevier Science B.V.

Journal of Comparative Neurology, 1994

The developmental, genetic, and biochemical similarities that have been observed between the cere... more The developmental, genetic, and biochemical similarities that have been observed between the cerebellum and retina form the basis for ongoing investigations into retinal expression of cerebellar-specific proteins. We have examined the mouse, rat, rabbit, and human retina for expression of a protein that is present in parasagittal Purkinje cell strips and that is recognized by the antibody Zebrin-II. This protein has recently been identified as a member of the aldolase C isoenzymes. Western blotting and immunocytochemistry have been used.The monoclonal antibody Zebrin-II recognized a prominent 36 kDa protein band on immunoblots of both the cerebellum and the retina of the examined species. Immunocytochemistry showed that, in the three nonhuman species, cells were stained in the ganglion cell layer (GCL). In addition, in the mouse and rabbit, cells in the inner nuclear layer (INL) were also labeled. Except for the visual streak, there were more immunopositive cells in the rabbit GCL and INL than in corresponding areas of the mouse retina. In the human, in contrast to the other species, the photoreceptor cell layer was strongly aldolase C immunoreactive. In the h all species except for the rat, the photoreceptor inner segments also displayed a weak labeling.The results show that this aldolase C isoenzyme is another protein that is selectively expressed by the cerebellum: and retina. Furthermore, the retinal expression is species specific, and this pattern seems to show a good correlation with the oxygenation level of the individual compartments. The indication that this aldolase C isoenzyme has specific developmental functions in the retina provides additional clues for our understanding of cerebellar organization. © 1994 Wiley-Liss, Inc.

Brain Research, 1997

Journal of Insect Physiology, 1999

Journal of Biological Rhythms, 2005

Journal of The Royal Society of Medicine, 2003

Journal of Sleep Research, 2002

Chronobiology International, 2009

Chronobiology International, 2007

Journal of Human Genetics, 2006

Molecular Brain Research, 1999

Journal of Sleep Research, 2007

Journal of Biological Rhythms, 2005

Journal of Molecular Evolution, 2006

European Journal of Neuroscience, 2004

Molecular Brain Research, 1998

Journal of Comparative Neurology, 1994