CRY1
Cryptochrome-1 [PHLL1]
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Our earlier studies demonstrated that cysteine414- (zinc-binding site of mCRY1-) alanine mutant mCRY1 transgenic mice (Tg mice) exhibit diabetes characterized by the reduction of [i]β[/i]-cell proliferation and by [i]β[/i]-cell dysfunction, presumably caused by senescence-associated secretory phenotype- (SASP-) like characters of islets. Earlier studies also showed that atypical duct-like structures in the pancreas developed age-dependently in Tg mice. Numerous reports have described that karyopherin alpha 2 (KPNA2) is highly expressed in cancers of different kinds. However, details of the expression of KPNA2 in pancreatic ductal atypia and in normal pancreatic tissues remain unclear. To assess the feature of the expression of KPNA2 in the development of the ductal atypia and islet architectures, we scrutinized the pancreas of Tg mice histopathologically. Results showed that considerable expression of KPNA2 was observed in pancreatic [i]β[/i]-cells, suggesting its importance in maintaining the functions of [i]β[/i]-cells. In mature stages, the level of KPNA2 expression was lower in islets of Tg mice than in wild-type controls. At 4 weeks, the expression levels of KPNA2 in islets of Tg mice were the same as those in wild-type controls. These results suggest that the reduction of KPNA2 might contribute to [i]β[/i]-cell dysfunction in mature Tg mice. Additionally, the formation of mucin-producing intra-islet ducts, islet fibrosis, and massive T cell recruitment to the islet occurred in aged Tg mice. In exocrine areas, primary pancreatic intraepithelial neoplasias (PanINs) with mucinous pancreatic duct glands (PDGs) emerged in aged Tg mice. High expression of KPNA2 was observed in the ductal atypia. By contrast, KPNA2 expression in normal ducts was quite low. Thus, upregulation of KPNA2 seemed to be correlated with progression of the degree of atypia in pancreatic ductal cells. The SASP-like microenvironment inside islets might play stimulatory roles in the formation of ductal metaplasia inside islets and in islet fibrosis in Tg mice.
MeSH Terms
- Aging
- Animals
- Cryptochromes
- Diabetes Mellitus, Experimental
- Fibrosis
- Gene Expression Profiling
- Gene Expression Regulation
- Immunohistochemistry
- Islets of Langerhans
- Male
- Mice
- Mice, Transgenic
- Mutation
- Pancreas
- Pancreatic Ducts
- Phenotype
- Up-Regulation
- alpha Karyopherins
The discovery of musculoskeletal tissues, including muscle, tendons, and cartilage, as peripheral circadian clocks strongly implicates their role in tissue-specific homeostasis. Age-related dampening and misalignment of the tendon circadian rhythm and its outputs may be responsible for the decline in tendon homeostasis. It is unknown which entrainment signals are responsible for the synchronization of the tendon clock to the light-dark cycle. We sought to examine any changes in the expression levels of core clock genes (BMAL1, CLOCK, PER2, CRY1, and NR1D1) in healthy human patellar tendon biopsies obtained from three different intervention studies: increased physical activity (leg kicks for 1 h) in young, reduced activity (2 weeks immobilization of one leg) in young, and in old tendons. The expression level of clock genes in human tendon in vivo was very low and a high variation between individuals was found. We were thus unable to detect any differences in core clock gene expression neither after acute exercise nor immobilization. We are unable to find evidence for an effect of exercise or immobilization on circadian clock gene expression in human tendon samples.
MeSH Terms
- Adult
- Aged
- Circadian Rhythm Signaling Peptides and Proteins
- Exercise
- Humans
- Immobilization
- Male
- Patellar Ligament
Keywords
- Aging
- Circadian clock
- Exercise
- Gene expression
- Immobilization
- Tendon
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
Keywords
- Circadian clock genes
- Granulosa cells
- Reproductive aging
Polyamines are essential polycations present in all living cells. Polyamine levels are maintained from the diet and de novo synthesis, and their decline with age is associated with various pathologies. Here we show that polyamine levels oscillate in a daily manner. Both clock- and feeding-dependent mechanisms regulate the daily accumulation of key enzymes in polyamine biosynthesis through rhythmic binding of BMAL1:CLOCK to conserved DNA elements. In turn, polyamines control the circadian period in cultured cells and animals by regulating the interaction between the core clock repressors PER2 and CRY1. Importantly, we found that the decline in polyamine levels with age in mice is associated with a longer circadian period that can be reversed upon polyamine supplementation in the diet. Our findings suggest a crosstalk between circadian clocks and polyamine biosynthesis and open new possibilities for nutritional interventions against the decay in clock's function with age.
MeSH Terms
- ARNTL Transcription Factors
- Aging
- Animals
- CLOCK Proteins
- Circadian Clocks
- Circadian Rhythm
- Cryptochromes
- Feeding Behavior
- Humans
- Mice
- NIH 3T3 Cells
- Period Circadian Proteins
- Polyamines
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