Researchers uncover how certain transcription pathways can control dental cell differentiation and tooth root formation

Tooth root development relies on precise coordination of cellular signals, yet the underlying mechanisms remain unclear. Researchers have uncovered how two proteins, Gli2 and Gli3, work together to control signaling and differentiation in dental progenitor cells. Their findings show that disrupting this interaction impairs cell proliferation and differentiation, leading to defective root formation. The study highlights a key molecular pathway that could inform future strategies for dental regeneration and craniofacial repair.

Tooth root formation is a critical process that anchors teeth within the jaw and ensures proper oral function. This complex developmental event depends on cranial neural crest cells, a group of multipotent cells that give rise to many cranial and facial tissues. These cells must precisely balance proliferation and differentiation to form functional tooth roots. Although Hedgehog (HH) signaling plays a central role in guiding these processes, the molecular mechanisms that govern how progenitor cells interpret these signals during development remain poorly understood.

To this end, a team of researchers led by Professor Xianglong Han, along with Professor Junjun Jing, both from the National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology at Sichuan University, China, combined transgenic mouse models with bioinformatic analyses to uncover the underlying cell signaling mechanism responsible for dental cell differentiation. Specifically, the researchers investigated how Gli transcription factors regulate tooth root formation in dental mesenchymal progenitor cells in mice. Their findings were published on March 12, 2026, in Volume 18 of International Journal of Oral Science.

The study focused on two key transcription factors, Gli2 and Gli3, which act as major mediators in the HH signaling pathway. “By selectively deleting these genes in Gli1-positive progenitor cells, we were able to assess their individual and combined roles in root development. While deletion of Gli2 alone produced minimal effects, the loss of Gli3 resulted in shortened tooth roots and reduced bone formation, ”says Prof. Han.

Notably, simultaneous deletion of both Gli2 and Gli3 genes led to severe root dysplasia, with nearly half the normal root length lost. These findings indicate that Gli2 and Gli3 function synergistically to regulate tooth root morphogenesis.

Further investigation revealed that the observed defects were linked to impaired cellular processes within the dental mesenchyme. The absence of Gli2 and Gli3 disrupted the proliferation of progenitor cells and significantly reduced their ability to differentiate into key cell types, including odontoblasts, periodontal ligament cells, and osteoblasts. As a result, the structural integrity and functional organization of the tooth root were compromised. Importantly, these effects were specific to mesenchymal cells, as deletion of the same genes in the dental epithelium did not produce similar abnormalities.

At the molecular level, the researchers uncovered a critical interaction between HH signaling and transforming growth factor beta (TGF-β) signaling. They found that Gli2 and Gli3 directly regulated the expression of Acvr2b, a receptor involved in the TGF-β pathway. Loss of these transcription factors led to reduced activation of key downstream effectors in the signaling cascade. This disruption ultimately impaired the signaling environment necessary for proper cell fate decisions in tooth root progenitor cells.

To test whether restoring this pathway could reverse the defects, the team pharmacologically activated TGF-β signaling in the mutant models. This intervention partially rescued tooth root length, improved bone formation, and restored differentiation of key cell types. These findings confirm that the interaction between HH and TGF-β signaling is essential for normal root development.

Beyond immediate findings, the study has important implications for both basic research and clinical applications. In the short term, it provides new insights into the molecular basis of dental abnormalities and craniofacial developmental disorders. It may also guide future studies exploring how disruptions in signaling pathways contribute to congenital defects. In the longer term, this research could support the development of regenerative approaches aimed at repairing or rebuilding damaged tooth roots.

Prof. Jing adds, “Understanding how signaling crosstalk governs progenitor cell behavior opens new possibilities for designing targeted therapies in regenerative dentistry and craniofacial medicine.”

The findings may also encourage interdisciplinary collaborations across developmental biology, stem cell research, and tissue engineering. By revealing a key regulatory axis controlling cell fate decisions, this work provides a foundation for future studies investigating similar mechanisms in other organs and systems. Ultimately, this research advances our understanding of how complex signaling networks shape organ development and offers promising directions for improving dental health and regenerative treatment strategies in the years ahead.


Reference
Title of original paper: Gli2 and Gli3 synergistically mediate HH-TGF-β crosstalk in mesenchymal progenitor cells to orchestrate tooth root morphogenesis
Journal: International Journal of Oral Science
DOI: https://doi.org/10.1038/s41368-026-00427-6

About Sichuan University, China
Sichuan University, located in Chengdu, China, is a prestigious public research university founded in 1896 and affiliated with the Ministry of Education. It offers a comprehensive range of disciplines across sciences, engineering, medicine, humanities, and social sciences, supported by numerous state key laboratories and research centers. The university hosts over 70,000 students and maintains strong global collaborations with institutions across more than 30 countries. Known for its excellence in research and innovation, several of its disciplines rank among the top globally. With modern campuses and advanced facilities, Sichuan University continues to drive academic and scientific progress.
Website: https://en.scu.edu.cn/

About Professor Xianglong Han from Sichuan University, China
Dr. Xianglong Han is a Professor, chief physician, and doctoral supervisor at the West China School/Hospital of Stomatology, Sichuan University. He is a member of the Edward H. Angle Society of Orthodontists and vice chairman of the Chinese Society of Esthetic Dentistry under the Chinese Stomatological Association. His research focuses on tooth movement, periodontal tissue remodeling, and biomineralization. He has led seven National Natural Science Foundation of China projects, published over 100 scientific papers, contributed to 10 monographs, and holds 30 national patents. He has received awards from leading international and national scientific organizations.

About Professor Junjun Jing from Sichuan University, China
Dr. Junjun Jing is a Professor at the State Key Laboratory of Oral Diseases and the National Clinical Research Center for Oral Diseases at Sichuan University, Chengdu, China. He has authored 74 scientific publications in the field of craniofacial biology. His research expertise includes craniofacial development, stem cell biology, and tissue regeneration. His work focuses on uncovering the molecular and cellular mechanisms that regulate craniofacial morphogenesis and related diseases. Professor Jing’s contributions have advanced understanding in developmental biology and regenerative medicine, particularly in dental and skeletal systems, establishing him as a respected expert in the field.

Funding information
The authors gratefully acknowledge the support from the National Natural Science Foundations of China (U24A20712, 82271022, and 82370915), National Key R&D Program of China (2024YFC2510700), and Innovative Research Group of the National Natural Science Foundation of Sichuan Province (2025NSFTD0026).