The software atlas technique described the p63 phenotype as a combination of developmental delay (i.e., heterochrony) and malformation (i.e., pathological shape; failed organogenesis). This study identifies for the first time global and local roles for p63 in prenatal growth and development. Developmental Dynamics 247:779-787, 2018. © 2018 Wiley Periodicals, Inc.

For humans and other mammals to eat effectively, teeth must develop properly inside the jaw. Deciphering craniodental integration is central to explaining the timely formation of permanent molars, including third molars which are often impacted in humans, and to clarifying how teeth and jaws fit, function and evolve together. A factor long-posited to influence molar onset time is the jaw space available for each molar organ to form within. Here, we tested whether each successive molar initiates only after a minimum threshold of space is created via jaw growth. We used synchrotron-based micro-CT scanning to assess developing molars in situ within jaws of C57BL/6J mice aged E10 to P32, encompassing molar onset to emergence. We compared total jaw, retromolar and molar lengths, and molar onset times, between upper and lower jaws. Initiation time and developmental duration were comparable between molar upper and lower counterparts despite shorter, slower-growing retromolar space in the upper jaw, and despite size differences between upper and lower molars. Timing of molar formation appears unmoved by jaw length including space. Conditions within the dental lamina likely influence molar onset much more than surrounding jaw tissues. We theorize that molar initiation is contingent on sufficient surface area for the physical reorganization of dental epithelium and its invagination of underlying mesenchyme.

Background p63 is an evolutionarily ancient transcription factor essential to vertebrate tooth development. Our recent gene expression screen comparing wild‐type and “toothless” p63−/− mouse embryos implicated in tooth development several new genes that we hypothesized act downstream of p63 in dental epithelium, where p63 is also expressed. Results Via in situ hybridization and immunohistochemistry, we probed mouse embryos (embryonic days 10.5‐14.5) and spotted gar fish embryos (14 days postfertilization) for these newly linked genes, Cbln1, Cldn23, Fermt1, Krt15, Pltp and Prss8, which were expressed in mouse and gar dental epithelium. Loss of p63 altered expression levels but not domains. Expression was comparable between murine upper and lower tooth organs, implying conserved gene functions in maxillary and mandibular dentitions. Our meta‐analysis of gene expression databases supported that these genes act within a p63‐driven gene regulatory network important to tooth development in mammals and more evolutionary ancient vertebrates (fish, amphibians). Conclusions Cbln1, Cldn23, Fermt1, Krt15, Pltp, and Prss8 were expressed in mouse and fish dental epithelium at placode, bud, and/or cap stages. We theorize that these genes participate in cell‐cell adhesion, cell polarity, and extracellular matrix signaling to support dental epithelium integrity, folding, and epithelial‐mesenchymal cross talk during tooth development.

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