Evc Regulates a Symmetrical Response to Shh Signaling in Molar Development

Abstract

Tooth morphogenesis involves patterning through the activity of epithelial signaling centers that, among other molecules, secrete Sonic hedgehog (Shh). While it is known that Shh responding cells need intact primary cilia for signal transduction, the roles of individual cilia components for tooth morphogenesis are poorly understood. The clinical features of individuals with Ellis-van Creveld syndrome include various dental anomalies, and we show here that absence of the cilial protein Evc in mice causes various hypo- and hyperplasia defects during molar development. During first molar development, the response to Shh signaling is progressively lost in Evc-deficient embryos and, unexpectedly, the response consistently disappears in a buccal to lingual direction. The important role of Evc for establishing the buccal-lingual axis of the developing first molar is also supported by a displaced activity of the Wnt pathway in Evc mutants. The observed growth abnormalities eventually manifest in first molar microdontia, disruption of molar segmentation and symmetry, root fusions, and delayed differentiation. Analysis of our data indicates that both spatially and temporally disrupted activities of the Shh pathway are the primary cause for the variable dental anomalies seen in patients with Ellis-van Creveld syndrome or Weyers acrodental dysostosis.

Suppression of epithelial differentiation by Foxi3 is essential for molar crown patterning

“…In the Shh cKO, also the M1 and M2 fuse and the molars have shallow cusps with an abnormal pattern (Dassule et al, 2000). Deletion of other Shh pathway components, Smo or Evc, leads to milder molar fusion phenotypes (Gritli-Linde et al, 2002;Nakatomi et al, 2013). Our hanging drop induction experiment suggests that Foxi3 might be a downstream target of Shh, and therefore Foxi3 deletion could lead to a similar phenotype to the mutations in the Shh pathway components.…”

An Nfic-hedgehog signaling cascade regulates tooth root development

“…Conditional knockout of Shh or Smo in dental epithelium both caused fused and abnormal molar tooth germs (Dassule et al, 2000;Gritli-Linde et al, 2002). Evc and Ift88, genes related to cilia and Hh signal transduction, also regulated normal patterning of molar tooth germ (Nakatomi et al, 2013;Ohazama et al, 2009). Our study suggests that Hh also plays a key role in later stages of tooth development.…”

Primary Cilia and Intraflagellar Transport Proteins in Bone and Cartilage

“…Dental anomalies have consistently been reported in several ciliopathies, such as Ellis-van Creveld syndrome (Haycraft and Serra 2008;Nakatomi et al 2013). Evc -/-mice develop smaller first molars (Ruiz-Perez et al 2007), resulting from the progressive loss of Shh signaling that causes delayed differentiation (Nakatomi et al 2013).…”

“…Dental anomalies have consistently been reported in several ciliopathies, such as Ellis-van Creveld syndrome (Haycraft and Serra 2008;Nakatomi et al 2013). Evc -/-mice develop smaller first molars (Ruiz-Perez et al 2007), resulting from the progressive loss of Shh signaling that causes delayed differentiation (Nakatomi et al 2013). Deletion of Kif3a in dental mesenchyme (Wnt1-Cre;Kif3a fl/fl ) totally disrupts incisor development but enlarges molars with reduced Hh signaling and increased Wnt signaling, implying that primary cilia balance the Hh and Wnt signaling between dental epithelia and mesenchyme for tooth development (Kolpakova-Hart et al 2007;Liu et al 2014).…”