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Cryptochrome-2 [KIAA0658]


Is the aging human ovary still ticking?: Expression of clock-genes in luteinized granulosa cells of young and older women.

It has been shown - mostly in animal models - that circadian clock genes are expressed in granulosa cells and in corpora luteum and might be essential for the ovulatory process and steroidogenesis. We sought to investigate which circadian clock genes exist in human granulosa cells and whether their expression and activity decrease during aging of the ovary. Human luteinized granulosa cells were isolated from young (age 18-33) and older (age 39-45) patients who underwent in-vitro fertilization treatment. Levels of clock genes expression were measured in these cells 36 h after human chorionic gonadotropin stimulation. Human luteinized granulosa cells were isolated from follicular fluid during oocyte retrieval. The mRNA expression levels of the circadian genes CRY1, CRY2, PER1, PER2, CLOCK, ARNTL, ARNTL2, and NPAS2 were analyzed by quantitative polymerase chain reaction. We found that the circadian genes CRY1, CRY2, PER1, PER2, CLOCK, ARNTL, ARNTL2, and NPAS2, are expressed in cultured human luteinized granulosa cells. Among these genes, there was a general trend of decreased expression in cells from older women but it reached statistical significance only for PER1 and CLOCK genes (fold change of 0.27 ± 0.14; p = 0.03 and 0.29 ± 0.16; p = 0.05, respectively). This preliminary report indicates that molecular circadian clock genes exist in human luteinized granulosa cells. There is a decreased expression of some of these genes in older women. This decline may partially explain the decreased fertility and steroidogenesis of reproductive aging.

MeSH Terms

  • Adolescent
  • Adult
  • Aging
  • Circadian Rhythm Signaling Peptides and Proteins
  • Female
  • Gene Expression
  • Granulosa Cells
  • Humans
  • Luteinization
  • Middle Aged
  • RNA, Messenger
  • Young Adult


  • Circadian clock genes
  • Granulosa cells
  • Reproductive aging

Role of Aging and Hippocampus in Time-Place Learning: Link to Episodic-Like Memory?

With time-place learning (TPL), animals link an event with the spatial location and the time of day (TOD). The what-where-when TPL components make the task putatively episodic-like in nature. Animals use an internal sense of time to master TPL, which is circadian system based. Finding indications for a role of the hippocampus and (early) aging-sensitivity in TPL would strengthen the episodic-like memory nature of the paradigm. Previously, we used C57Bl/6 mice for our TPL research. Here, we used CD1 mice which are less hippocampal-driven and age faster compared to C57Bl/6 mice. To demonstrate the low degree of hippocampal-driven performance in CD1 mice, a cross maze was used. The spontaneous alternation test was used to score spatial working memory in CD1 mice at four different age categories (young (3-6 months), middle-aged (7-11 months), aged (12-18 months) and old (>19 months). TPL performance of middle-aged and aged CD1 mice was tested in a setup with either two or three time points per day (2-arm or 3-arm TPL task). Immunostainings were applied on brains of young and middle-aged C57Bl/6 mice that had successfully mastered the 3-arm TPL task. In contrast to C57Bl/6 mice, middle-aged and aged CD1 mice were less hippocampus-driven and failed to master the 3-arm TPL task. They could, however, master the 2-arm TPL task primarily via an ordinal (non-circadian) timing system. c-Fos, CRY2, vasopressin (AVP), and phosphorylated cAMP response element-binding protein (pCREB) were investigated. We found no differences at the level of the suprachiasmatic nucleus (SCN; circadian master clock), whereas CRY2 expression was increased in the hippocampal dentate gyrus (DG). The most pronounced difference between TPL trained and control mice was found in c-Fos expression in the paraventricular thalamic nucleus, a circadian system relay station. These results further indicate a key role of CRY proteins in TPL and confirm the limited role of the SCN in TPL. Based on the poor TPL performance of CD1 mice, the results suggest age-sensitivity and hippocampal involvement in TPL. We suspect that TPL reflects an episodic-like memory task, but due to its functional nature, also entail the translation of experienced episodes into semantic rules acquired by training.


  • aging
  • circadian
  • clock genes
  • cry
  • learning
  • memory
  • place
  • time

Association of osteoporosis with genetic variants of circadian genes in Chinese geriatrics.

This study was designed to investigate the association of circadian gene single nucleotide polymorphisms (SNPs) with the risk of osteoporosis. We found that the rs3781638 GG genotype was positively associated with osteoporosis prevalence in females, whereas the rs2292910 AC genotype was negatively associated with osteoporosis prevalence in a geriatric cohort. Studies have shown that disruption of endogenous circadian rhythms may increase the risk of developing type II diabetes and obesity, which are reportedly associated with osteoporosis (OP). Thus, abnormalities of circadian genes may indirectly induce OP. Here, we investigated the association of OP with 14 SNPs located in seven circadian genes. The research subjects, geriatric residents of Shanghai Minhang, China, diagnosed with OP (N = 171) or osteopenia (N = 226) or without specific diseases (N = 200), were genotyped for 14 genetic variants of circadian genes by competitive allele-specific polymerase chain reaction. The prevalence of polymorphisms among the subject groups and the association between the SNPs and osteoporosis were investigated. Among the 14 genotyped SNPs, we found an association between the CRY2 gene rs2292910 SNP and osteoporosis (r = -0.082, p = 0.045) in the geriatric cohort. We found a decreased risk between cryptochrome 2 rs2292910 and OP (A/C odds ratio = 0.647, p = 0.044) but an increased risk between MTNR1B rs3781638 and OP (G/G odds ratio = 2.058, p = 0.044). For the first time, we show that Cry 2 rs2292910 and MTNR1B rs3781638 are associated with osteoporosis in a Chinese geriatric cohort. Therefore, targeting the abnormalities of the CRY2 and MTNR1B genes may be a potential strategy to treat and/or to prevent osteoporosis.

MeSH Terms

  • Absorptiometry, Photon
  • Aged
  • Asian Continental Ancestry Group
  • Body Mass Index
  • Bone Density
  • Circadian Clocks
  • Circadian Rhythm Signaling Peptides and Proteins
  • Cryptochromes
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Osteoporosis
  • Polymorphism, Single Nucleotide
  • Receptor, Melatonin, MT2


  • Cryptochrome 2
  • Geriatrics
  • MTNR1B
  • Osteoporosis
  • SNP

Circadian clock proteins control adaptation to novel environment and memory formation.

Deficiency of the transcription factor BMAL1, a core component of the circadian clock, results in an accelerated aging phenotype in mice. The circadian clock regulates many physiological processes and was recently implicated in control of brain-based activities, such as memory formation and the regulation of emotions. Aging is accompanied by the decline in brain physiology, particularly decline in the response and adaptation to novelty. We investigated the role of the circadian clock in exploratory behavior and habituation to novelty using the open field paradigm. We found that mice with a deficiency of the circadian transcription factor BMAL1 display hyperactivity in novel environments and impaired intra- and intersession habituation, indicative of defects in short- and long-term memory formation. In contrast, mice double-deficient for the circadian proteins CRY1 and CRY2 (repressors of the BMAL1-mediated transcription) demonstrate reduced activity and accelerated habituation when compared to wild type mice. Mice with mutation in theClock gene (encoding the BMAL1 transcription partner) show normal locomotion, but increased rearing activity and impaired intersession habituation. BMAL1 is highly expressed in the neurons of the hippocampus - a brain region associated with spatial memory formation; BMAL1 deficiency disrupts circadian oscillation in gene expression and reactive oxygen species homeostasis in the brain, which may be among the possible mechanisms involved. Thus, we suggest that the BMAL1:CLOCK activity is critical for the proper exploratory and habituation behavior, and that the circadian clock prepares organism for a new round of everyday activities through optimization of behavioral learning.

MeSH Terms

  • ARNTL Transcription Factors
  • Aging
  • Animals
  • Biological Clocks
  • CLOCK Proteins
  • Cerebral Cortex
  • Circadian Rhythm
  • Cryptochromes
  • Exploratory Behavior
  • Habituation, Psychophysiologic
  • Hippocampus
  • Hyperkinesis
  • Memory
  • Mice
  • Mice, Knockout
  • Motor Activity
  • Reactive Oxygen Species