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

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

  • Development. 2024 Nov 1;151(21):dev202899. doi: 10.1242/dev.202899.
Xiaoyu Zheng 1 2,  Hongcan Huang 1 2,  Zhipeng Zhou 3,  Weihua Guo 4 5,  Guobin Yang 1,  Zhi Chen 1,  Di Chen 6 7,  YiPing Chen 8,  Guohua Yuan 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
  • 2 Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China.
  • 3 National Key Laboratory of Agricultural Microbiology, College of Life Sciences and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
  • 4 Yunnan Key Laboratory of Stomatology, Kunming Medical University, Kunming, Yunnan 610041, China.
  • 5 Department of Pediatric Dentistry, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan 610041, China.
  • 6 Research Center for Computer-aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
  • 7 Faculty of Pharmaceutical Sciences, Shenzhen Institutes of Advanced Technology, Shenzhen, Guangdong 518055, China.
  • 8 Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
PMID: 39344774 DOI: 10.1242/dev.202899
Abstract

Hertwig's epithelial root sheath (HERS) interacts with dental apical mesenchyme and guides development of the tooth root, which is integral to 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 the mTORC1 subunit Rptor or pharmacological inhibition of Shh signaling can rescue the root defects in Axin1 mutant mice. Collectively, our data suggest that, independently of canonical Wnt signaling, Axin1 controls ribosomal biogenesis and selective mRNA translation programs via AKT1-mTORC1 signaling during tooth root development.

Keywords

Axin1; Hertwig's epithelial root sheath; Protein synthesis; Ribosome; Tooth root development.

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