Disease relevance of Per1

• Transfection of the constitutively-active CaM kinase IIdelta greatly increased mPer1 promoter activity in NG108-15 cells and increased activity slightly but significantly in NB2A and C6 glioma cells [1].
• Mouse Per1 (mPer1) RNA was localized to inner nuclear and ganglion cell layers but was absent in the outer nuclear (photoreceptor) layer [2].
• Three monoclonal IgG of different subclasses (IgG1, IgG2, and IgG4) and one IgA1 were isolated from the serum of patient Per suffering from an immunocytic sarcoma [3].
• The goal was to assess the role of metabolism in the sex and species dependence of susceptibility to Per-induced toxicity [4].
• The mPer1 clock gene expression in the rd mouse suprachiasmatic nucleus is affected by the retinal degeneration [5].

Psychiatry related information on Per1

• Mice homozygous for the targeted allele of either mPer1 or mPer2 had severely disrupted locomotor activity rhythms during extended exposure to constant darkness [6].
• Although mPer1 and mPer2 represent key elements of the molecular clock in the SCN, they are not required for homeostatic regulation of the daily amounts of waking, SWS, or REM sleep [7].
• Here we show that the mouse homologues of the Drosophila Per gene, mPer1 and mPer2, modulate cocaine sensitization and reward, two phenomena extensively studied in humans and animals because of their importance for drug abuse [8].
• The role of mPer1 in morphine dependence in mice [9].
• Despite reported differences in maximal levels and timing of mCry1, mPer1, and mPer2 RNAs, the corresponding protein levels peaked simultaneously during late day, suggesting a codependency for their stabilization and/or nuclear entry [10].

High impact information on Per1

• Mice lacking molecular-clock components (Per and Cry), or lacking Per genes in osteoblasts, display high bone mass, suggesting that bone remodeling may also be subject to circadian regulation [11].
• Moreover, Per-deficient mice experience a paradoxical increase in bone mass following leptin intracerebroventricular infusion [11].
• Moreover, the mutants fail to show acute induction of mPer1 and mPer2 by nocturnal illumination [12].
• Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms [13].
• Mice carrying a null mutation in the Period 1 (mPer1) gene were generated using embryonic stem cell technology [14].

Chemical compound and disease context of Per1

• The renal toxicity of Per is likely mediated by a glutathione-dependent bioactivation reaction [15].

Biological context of Per1

• The promoter regions of the Per1, Per2 and Cry1 genes exhibit circadian rhythms in H3 acetylation and RNA polymerase II binding that are synchronous with the corresponding steady-state messenger RNA rhythms [16].
• Circadian and light-induced transcription of clock gene Per1 depends on histone acetylation and deacetylation [17].
• Here we show that Per1 gene expression in the testis is constant over a 24-h period and that the Per1 transcript is expressed at a level higher than the peak values of the Per1 oscillations observed for other tissues [18].
• Here we investigated the expression of two clock genes (Per1, Cry2) and the level of phosphorylated (p) cyclic AMP response element binding protein (CREB) in retinae of melatonin-deficient (C57BL) with an intact retina and melatonin-proficient (C3H) mice with degenerated outer nuclear layer [19].
• We thus propose that the CKIepsilon-binding domain is critical not only for mPER phosphorylation but also for a functioning circadian clock [20].

Anatomical context of Per1

• Per1 expression is not altered in testes from Clock mutant mice, suggesting that CLOCK does not activate Per1 in male germ cells, in contrast to what it does in other mouse tissues [18].
• Strikingly, Per1 is restricted primarily to step 7 to 10 spermatids and thus appears to be developmentally regulated [18].
• Mammalian circadian clock genes Per1 and Per2 are rhythmically expressed not only in the suprachiasmatic nucleus where the mammalian circadian clock exists, but also in other brain regions and peripheral tissues [21].
• In this experiment, we examined the day--night pattern of expression of Per1 and Per2 mRNA in the mouse SCN and cerebral cortex on embryonic day 17, postnatal day 3, and in young adult mice under a light-dark cycle [22].
• Although the caudate/putamen (CPu) expresses mPer1 and/or mPer2 mRNA, the function of these genes in this nucleus has not yet been elucidated [23].

Associations of Per1 with chemical compounds

• Ethanol self-administration and reinstatement of ethanol-seeking behavior in Per1 ( Brdm1 ) mutant mice [24].
• Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock [6].
• The present results demonstrate that activation of both NMDA and D1 receptors is necessary to produce MAP-induced mPer1 expression in the CPu [23].
• The present study suggests that a stress-induced disturbance of circadian corticosterone secretion may be associated with the stress-induced expression of mPer1 mRNA in the PVN [25].
• Forced swimming, immobilization, and lipopolysaccharide injection elevated mPer1 gene expression in the PVN but not in the SCN or liver [25].

Regulatory relationships of Per1

• Addition of pituitary adenylate cyclase-activating polypeptide-38 to the medium also induced transient Per1 gene expression [21].
• Furthermore, mPer2 is co-expressed with mPer1 in single SCN cells [26].
• DEC1 and DEC2 can inhibit CLOCK:BMAL1 transactivation of the clock gene Per1, suggesting that these transcription factors may help regulate circadian timing [27].
• These results suggest that Per1 can be a potential stress marker and that a third pathway of Per1 transcriptional control may exist in addition to the clock-regulated CLOCK-BMAL1/E-box and light-responsive cAMP-responsive element-binding protein/cAMP-responsive element pathways [28].
• Our data reveal that GnRH-induced mPer1 expression is blocked following acute exposure to a MAPK kinase inhibitor [29].

Other interactions of Per1

• The magnitude and time course of acute light induction in the suprachiasmatic nuclei of the only known light-induced core clock genes, Per1 and Per2, are not affected by the Clock/+ mutation [30].
• Furthermore, Per1 and Cry2 oscillations in the SCN were phase advanced by 1 and 3 h, respectively, in hypocalorie- but not in normocalorie-fed mice [31].
• Transcript levels for each of these five genes fall at the two-cell stage, but are restored rapidly for Per1, Cry1 and Bmal1, presumptively by zygotic gene expression [32].
• Three putative mammalian homologues (mPer1, mPer2 and mPer3) of the Drosophila circadian clock gene period (per) have been identified [33].
• The aim of the study was to test whether mPer, mCry, Clock, and Bmal1 are rhythmically expressed in the mouse PT and how the absence of melatonin receptors affects clock gene expression [34].

Analytical, diagnostic and therapeutic context of Per1

• RNase protection assay and in situ hybridization revealed in both strains a rhythm in transcript levels for Per1 with a peak at zeitgeber time (ZT) 08, but not for Cry2 [19].
• The induced circadian oscillation of Per genes after treatment with high concentrations of serum or various drugs in cultured cells suggests the ubiquitous existence of the oscillatory mechanism [21].
• We used a dispersed primary cell culture made up of mouse cerebellar granule cells to examine the stimuli inducing the mPer genes and their signaling pathways in neuronal tissues expressing mPer genes [21].
• The genotypes did not differ in the effect of SD on the occipital EEG, while the effect on the frontal EEG was initially diminished in both mPer mutants [35].
• Mice were injected (s.c.) with fluorogold (FG) in order to label neuroendocrine cells and brain sections were double-labelled for either FG and Per1 mRNA (labelled by GFP immunostaining) or FG and PER1 protein using fluorescence immunocytochemistry [36].

References