Primary Cilia Integrate Hedgehog and Wnt Signaling during Tooth Development

Abstract

Many ciliopathies have clinical features that include tooth malformations but how these defects come about is not clear. Here we show that genetic deletion of the motor protein Kif3a in dental mesenchyme results in an arrest in odontogenesis. Incisors are completely missing, and molars are enlarged in Wnt1 Cre+ Kif3a fl/fl embryos. Although amelogenesis and dentinogenesis initiate in the molar tooth bud, both processes terminate prematurely. We demonstrate that loss of Kif3a in dental mesenchyme results in loss of Hedgehog signaling and gain of Wnt signaling in this same tissue. The defective dental mesenchyme then aberrantly signals to the dental epithelia, which prompts an upregulation in the Hedgehog and Wnt responses in the epithelia and leads to multiple attempts at invagination and an expanded enamel organ. Thus, the primary cilium integrates Hedgehog and Wnt signaling between dental epithelia and mesenchyme, and this cilia-dependent integration is required for proper tooth development.

<b>Developmental changes in primary cilia in the mouse tooth germ and oral </b><b>cavity </b>

“…Bar: 1 μm and Wnt families (20). In particular, it is known that the primary cilia are associated with Shh and Wnt signaling during tooth development (7). Therefore, our data further support the possibility that the primary cilia are involved in the epithelium-mesenchymal interaction in the enamel knot.…”

“…The primary cilia play critical roles associated with the epithelium-mesenchyme interaction in various tissues, including the tooth germ (2,7,17). Accumulating evidence shows that many growth factors/ receptors and cross-talk via these factors between adjacent tissues precisely regulate tooth development.…”

“…Primary cilia in the tooth germ have been investigated using animal models or tissue cultures. Here, tooth development involves a typical epithelial-mesenchymal interaction, and accumulating evidence indicates that the primary cilia may take a leading part in such interaction (7). Electron microscopic observation of the centriole and associated Golgi apparatus in the differentiating ameloblasts of the rat showed that the movement and separation of ciliated centrioles affected the morphological and functional differentiation of ameloblasts (16).…”

Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity (Review)

“…The synergetic interaction was postulated by Day et al (76), who reported that Ihh signaling is activated at an early stage of osteoblast maturation during fracture repair, and that Wnt signaling is subsequently upregulated in differentiated osteoblasts. Further research has indicated that the deletion of the motor protein kinesin family member 3A in dental mesenchyme results in the suppression of Hh and activation of Wnt, affecting incisor and molar development (77). These findings may reveal as association between the two signaling pathways at the gene level.…”

Role of Primary Cilia in Odontogenesis

“…Similarly, tooth buds from Wnt1-cre Kif3a f/f mice exhibit a loss of HH signaling and a concomitant gain of WNT/β-catenin signaling in the dental mesenchyme. The gain of Wnt signaling in the mesenchyme has a secondary effect on the dental epithelium, where it increases proliferation and results in multiple invaginations instead of single secondary enamel knot (Liu et al 2014). These data suggest that the primary cilium integrates WNT and SHH signaling between epithelium and mesenchyme during odontogenesis (Liu et al 2014).…”