Abstract
Cdkn1c, a member of the Cip/Kip cyclin-dependent kinase inhibitor family, is critically involved in regulating cell cycle and cellular differentiation during development in mammals. However, the functional role of Cdkn1c and the underlying mechanisms by which Cdkn1c affects odontogenesis remain largely unknown. In our study, we found that Cdkn1c expression dynamically changes from embryonic day 11.5 (E11.5) to postnatal day 3 (P3), and exhibits tissue-specific expression profiles. Evaluation of CDKN1C protein by immunohistochemistry and western blot, revealed that CDKN1C protein expression peaks at P3 and then is reduced at P5 and P7. Interestingly, we observed that CDKN1C expression is higher in immature odontoblasts than preodontoblasts, is lower in mature odontoblasts, and is practically absent from ameloblasts. We evaluated cell cycle progression to further investigate the mechanisms underlying CDKN1C-mediated regulation of odontogenesis, and found that pRB, cyclin D1 and CDK2 expression decreased from P1 to P3, and reduced at P5 and P7. In addition, we observed increased methylation of KvDMR1 at P1 and P3, and reduced KvDMR1 methylation at P5 and P7. However, the methylation levels of Cdkn1c-sDMR were relatively low from P1 to P7. In summary, we demonstrated that Cdkn1c expression and methylation status may be involved in early postnatal tooth development through regulating the cell cycle inhibition activity of Cdkn1c. Notably, Cdkn1c expression and methylation may associate with cell cycle exit and differentiation of odontoblasts.
Highlights
Tooth development involves a continuous and reciprocal series of interactions between dental epithelium and mesenchyme (Soukup et al 2008; Lee et al 2016); this cycle depends on the tightly regulated spatiotemporal expression of specific genes (Zhang et al 2009; Zhou et al 2017; Du et al 2016)
The present study demonstrated a role for p57 in murine tooth development at early postnatal stages
Data from the Gene expression omnibus (GEO) database showed that the expression pattern of p57 changes dynamically during different stages of tooth development (Fig. 1)
Summary
Tooth development involves a continuous and reciprocal series of interactions between dental epithelium and mesenchyme (Soukup et al 2008; Lee et al 2016); this cycle depends on the tightly regulated spatiotemporal expression of specific genes (Zhang et al 2009; Zhou et al 2017; Du et al 2016). Cell-cycle-associated genes, including genes of the Cip/Kip family of cyclin-dependent kinase inhibitors, are critical mediators and regulators of odontogenesis (Kumamoto et al 2001). Cip/Kip family genes are known to be important in differentiation of odontoblasts and ameloblasts (Lee et al 2009; Iwamoto et al 2017) and facilitate dental mineralization (Yin et al 2014). Little is known about the role of Cdkn1c, a recently discovered Cip/Kip family member, in odontogenesis.
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