p75NTR Promotes Circadian-Driven Mineralization During Tooth Development via CK2/PER2 Pathway

Circadian rhythm is an essential biological process that synchronises physiological activities with environmental light/dark cycles. However, its regulatory mechanisms in tooth development remain incompletely understood. Here, we investigated the role of the p75 neurotrophin receptor (p75NTR) in circadian rhythm regulation and daily mineralization during tooth development using immunofluorescence, circadian rhythm tracking, and genetic models. Spatiotemporal analysis of rat dental germs revealed that oscillatory expression patterns of p75NTR closely aligned with clock genes (Bmal1, Clock, Per1, Per2), mineralization-related factors, and odontogenesis-related factors. p75NTR knockout mice (p75NTR ^ExIII-/- ) exhibited reduced body weight, lower melatonin levels, delayed incisor eruption, decreased daily mineralization width, and downregulation of core clock genes. Mechanistically, p75NTR overexpression in immortalised stem cells from the dental apical papilla (iSCAPs) upregulated casein kinase 2 (CK2) expression, enhanced PER2 phosphorylation, and promoted nuclear p-PER2 accumulation, while CK2 inhibition partially reversed these effects. In vivo, CK2 inhibition via quinalizarin exacerbated incisor eruption defects in p75NTR ^ExIII-/- mice. These findings demonstrate that p75NTR regulates circadian-driven mineralization and tooth morphogenesis, probably via the CK2/PER2 pathway, providing critical insight into the interplay between the circadian rhythm and dental development.