Circadian Rhythm Regulates Development of Enamel in Mouse Mandibular First Molar

Abstract

Rhythmic incremental growth lines and the presence of melatonin receptors were discovered in tooth enamel, suggesting possible role of circadian rhythm. We therefore hypothesized that circadian rhythm may regulate enamel formation through melatonin receptors. To test this hypothesis, we examined expression of melatonin receptors (MTs) and amelogenin (AMELX), a maker of enamel formation, during tooth germ development in mouse. Using qRT-PCR and immunocytochemistry, we found that mRNA and protein levels of both MTs and AMELX in normal mandibular first molar tooth germs increased gradually after birth, peaked at 3 or 4 day postnatal, and then decreased. Expression of MTs and AMELX by immunocytochemistry was significantly delayed in neonatal mice raised in all-dark or all-light environment as well as the enamel development. Furthermore, development of tooth enamel was also delayed showing significant immature histology in those animals, especially for newborn mice raised in all daylight condition. Interestingly, disruption in circadian rhythm in pregnant mice also resulted in delayed enamel development in their babies. Treatment with melatonin receptor antagonist 4P-PDOT in pregnant mice caused underexpression of MTs and AMELX associated with long-lasting deficiency in baby enamel tissue. Electromicroscopic evidence demonstrated increased necrosis and poor enamel mineralization in ameloblasts. The above results suggest that circadian rhythm is important for normal enamel development at both pre- and postnatal stages. Melatonin receptors were partly responsible for the regulation.

Biological clocks and incremental growth line formation in dentine

“…Advances in gene editing technologies are permitting novel insights into circadian biology through targeted gene ablations (Tsuchiya et al ., 2016). Finally, others have hypothesized that the central nervous system may control incremental growth line formation through rhythmic melatonin secretion (Kumasaka et al ., 2010; Ji et al ., 2011; Tao et al ., 2016)—an intriguing possibility that remains to be tested.…”

To explore the influencing factors of amelogenesis imperfecta: the effect of melatonin on ALC cell line

“…We injected melatonin receptor antagonist into the peritoneum of BALB/c pregnant mice. It was found that the ameloblasts of mice at 7 and 10 days after birth were widely denatured, the degree of enamel mineralization was low, and the content of amelogenin was signi cantly reduced [7]. The previous experimental results show for the rst time that melatonin and its receptor system are related to the periodic growth and development of enamel.…”

“…The loss of circadian rhythm leads to the low degree of enamel mineralization in BALB/c neonatal mice [7].…”

Melatonin-Medicated Neural JNK3 Up-Regulation Promotes Ameloblastic Mineralization

“…Given the existence of enamel periodicity, we focused on the two stimuli that significantly regulate the biological rhythm of mammals, photoperiod and melatonin. Our previous studies revealed for the first time that melatonin-mediated circadian rhythm disturbance caused extensive degeneration of ameloblasts, low mineralization of enamel and significantly reduced amelogenin (AMELX) content in the first molar tooth embryo of 7 and 14 days postnatal mice (Tao et al, 2016). Circadian rhythms in mammals are regulated globally by the master clock in the suprachiasmatic nucleus (SCN), and locally by clock cells that control tissue-specific rhythmic outputs (Simmer et al, 2010).…”