Axin1 regulates tooth root development by inhibiting AKT1-mTORC1 activation and Shh translation in Hertwig's epithelial root sheath.

ABSTRACT

Hertwig's epithelial root sheath (HERS) interacts with dental apical mesenchyme and guides development of the tooth root, which is an integral part for the function of the whole tooth. However, the key genes in HERS essential for root development are understudied. Here we show that Axin1, a scaffold protein that negatively regulates canonical Wnt signaling, is strongly expressed in the HERS. Axin1 ablation in the HERS of mice leads to defective root development but in a manner independent of canonical Wnt signaling. Further studies reveal that Axin1 in the HERS negatively regulates the AKT1-mTORC1 pathway through binding to AKT1, leading to inhibition of ribosomal biogenesis and mRNA translation. Sonic hedgehog (Shh) protein, a morphogen essential for root development, is over synthesized by upregulated mTORC1 activity upon Axin1 inactivation. Importantly, either haploinsufficiency of mTORC1 subunit Raptor or pharmacologic inhibition of Shh signaling can rescue the root defects in Axin1 mutant mice. Collectively, our data suggest that, independent of canonical Wnt signaling, Axin1 controls ribosomal biogenesis and selective mRNA translation programs via AKT1-mTORC1 signaling during tooth root development.