Figure 1.
The non-visual pathway of light from the environment to the suprachiasmatic nucleus (SCN) and how it regulates the timing of the transcriptional/translational feedback loop (19). Once the light signal reaches the cells of the SCN, it is the induction of Per1 and Per2 gene expression that synchronises SCN timing with the environment.
Figure 2.
The differences in the timing of peak Per1 expression in central and peripheral clocks as measured in mice over the 24 hour period drawn from data in Yamanaka et al. (56). This demonstrates that under normal circumstances the timing of Per1 expression in each tissue is not precisely synchronised. Zeitgeber time (ZT) 0 is the time of exposure to the timegiver (in this case time of lights on). SCN=suprachiasmatic nucleus.
Table 1.
Human tissues where primary and secondary loop clock gene expression has been measured and the clock genes that were examined.
| System | Tissue/Cell | Clock Gene Measured | Reference | ||
|---|---|---|---|---|---|
| Integumentary | hair follicle | Bmal1 Per1 | Per2 Per3 | Rev-ERBα Rev-ERBβ | (58, 61, 62) |
| oral mucosa | Bmal1 Cry1 | Per1 Per2 | Rev-ERBα | (57, 63-65) | |
| skin | Bmal1 | Per1 | (57) | ||
| skin fibroblasts | Bmal1 Cry1 | Cry2 Per1 | Per2 Per3 | (66-69) | |
| skin keratinocytes | Bmal1 Cry1 Cry2 | Per 1 Per2 Per3 | Rev-ERBα RORα | (69) | |
| skin melanocytes | Bmal1 Cry1 Cry2 | Per 1 Per2 Per3 | Rev-ERBα | (69) | |
| epidermal stem cells | Bmal1 Cry1 Cry2 | Per1 Per2 Per3 | Rev-ERBα Rev-ERBβ | (59) | |
| Circulatory | whole blood | Clock Bmal1 Cry1 Cry2 | Per1 Per2 Per3 | Rev-ERBα Rev-ERBβ RORα | (70-74) |
| monocytes | Clock Bmal1 Cry1 | Cry2 Per1 Per2 | Per3 Rev-ERBα | (75) | |
| mononuclear blood cells | Clock Bmal1 Cry1 | Cry2 Per1 Per2α | Per3 Rev-ERBα | (76-85) | |
| leukocytes | Clock Bmal1 Cry1 | Cry2 Per1 Per2 | Per3 Rev-ERBα RORα | (58, 85-91) | |
| lymphocytes | Clock Bmal1 Cry1 | Cry2 Per1 Per2 | Per3 Rev-ERBα | (92) | |
| mast cells | Clock Bmal1 | Cry1 Per1 | Per2 | (93) | |
| eosinophils | Clock Bmal1 | Cry1 Per1 | Per2 | (93) | |
| CD4+ T-cells | Clock Bmal1 Cry1 | Cry2 Per2 Per3 | Rev-ERBα RORα | (94) | |
| polymorphonuclear cells | Cry1 Cry2 | Per1 Per2 | Per 3 | (83, 85) | |
| papillary muscle cells | Bmal1 Cry1 | Per1 Per2 | (95) | ||
| Endocrine | pancreatic islet cells | Clock Cry1 | Per3 Rev-ERBα | Rev-ERBβ | (96) |
| visceral adipose tissue | Clock Bmal1 | Cry1 | Per2 | (97, 98) | |
| subcutaneous adipose tissue | Clock Bmal1 | Cry1 | Per2 | (97, 98) | |
| Bone | CD4+ (haematopoietic) bone marrow cells | Clock Bmal1 | Cry1 Cry2 | Per2 Rev-ERBα | (99) |
| whole bone marrow cell samples | Clock Bmal1 | Cry1 Cry2 | Per2 Rev-ERBα | (99) | |
1 Note: Clock (circadian locomotor output cycles kaput); Bmal1 (brain and muscle arnt-like protein-1); Cry1 (cryptochrome 1); Cry2 (cryptochrome 2); Per1 (period 1); Per2 (period 2); Per3 (period 3); Rev-ERBα (reverse strand of ERBA alpha); Rev-ERBβ (reverse strand of ERBA beta); RORα (retinoic acid receptor-related orphan receptor alpha).
Table 2.
Evidence for the effect of identified entrainers on central and peripheral clock timing in humans and animal models.
| Tissue where the clock is found | Model | Entrainer | |||
|---|---|---|---|---|---|
| Light | Activity | Temperature | Food | ||
| SCN | Animal | Yes | No | No | No (timing) Yes (caloric restriction 66%) |
| Human | Yes | Yes (partial) | - | No (timing) Yes (caffeine) | |
| Liver | Animal | Yes - rat and mouse | Yes - mouse | Yes/no - mouse | Yes (timing) - rat and mouse Yes (caffeine) - mouse |
| Pineal Gland | Animal | Yes - rat | - | - | - |
| Adrenal Gland | Animal | Yes - rat and mouse | - | - | - |
| Human | Assumed (salivary cortisol) | - | - | - | |
| Heart | Animal | Yes - rat | - | - | Yes (timing) - rat and mouse |
| Skeletal Muscle | Animal | Yes - rat and mouse | Yes - mouse | - | - |
| Human | - | Possible | - | - | |
| Lung | Animal | Yes - mouse | Yes - mouse | - | Yes (timing) - rat Yes (caffeine) - mouse |
| Hair Follicle | Human | Yes | - | - | - |
| Kidney | Animal | - | - | No - mouse | No (timing) - mouse Yes (caffeine) - mouse |
| Submandibular Gland | Animal | - | - | No - mouse | - |
| Pancreas | Animal | - | - | - | Unsure (timing) - mouse |
