The Effects of Circadian Period Misalignment on Odontogenesis

Most cellular and physiological activities are temporally organized, with many following robust circadian oscillations over the 24-h day. Mineralized dental tissues formation during odontogenesis provide an especially tractable model to study such temporal control, as they display clear daily patterns of cell behavior and matrix accretion. In this pilot study, the temporal dimension of odontogenesis was examined using two complementary circadian knockout (KO) mouse models that exhibit opposing chronotypes; Cryptochrome1 (Cry1) KO, characterized by a 1-h shortened circadian period, and Cryptochrome2 (Cry2) KO, characterized by a 1-h lengthened period. Our data revealed distinct chrono/genotype-phenotype coupling across the dental tissues examined. Cry2 targeting resulted in more pronounced changes with significantly augmented dentin/cementum deposition accompanied by constricted pulp chambers. In enamel, targeting the Cry genes resulted in less noticeable effects with an accelerated early enamel matrix deposition rate observed in Cry2 mutants, while enamel mineralization was slightly slowed down, whereas targeting Cry1 resulted in an opposite pattern, slowed down secretion, and precocious enamel mineralization. Collectively, our results strongly suggest that there is a correlation between circadian period length and dental matrix proteins deposition, whereby longer periods favor elevated secretion rates while shorter periods result in a slightly reduced output. On the other hand, no similar effects were noted in mineral content, as mature enamel, bone, and dentin mineral densities did not differ significantly across the two KO models. Overall, this work identifies the cryptochrome 2 gene as a potent regulator of dentinogenesis and mandibular bone remodeling with a limited impact on amelogenesis. It also highlights intrinsic biological time as a fundamental axis along which the architecture of mineralized craniofacial tissues is patterned.