Abstract
Introduction
Mutations in
ALX1
cause frontonasal dysplasia type 3 (FND3), a congenital craniofacial disorder characterized by severe abnormalities of the frontonasal and midfacial structures. However, the role of
ALX1
in tooth development remains unclear.
Methods
We investigated the function of
Alx1
during mouse incisor morphogenesis using a neural crest-specific conditional knockout model. Histological, molecular, and transcriptomic analyses were performed to assess incisor morphogenesis, enamel knot formation, odontogenic gene expression, and signaling pathway activity.
Results
Mutant embryos exhibited complete agenesis of maxillary incisors and impaired development of mandibular incisors. Although tooth initiation was preserved, mutant maxillary incisors failed to progress through the bud-to-cap transition and lacked a discernible enamel knot. Transcriptomic profiling of E13.5 dental mesenchyme revealed alterations in odontogenic gene programs, including genes associated with BMP and Wnt signaling pathways. Consistent with these findings, expression of
Bmp4
and
Msx1
was markedly reduced, accompanied by impaired enamel knot-associated
Shh
expression. In parallel, canonical Wnt signaling activity, as indicated by active β-catenin and LEF1, was attenuated in mutant incisors.
Discussion
These findings identify
Alx1
as an essential regulator of enamel knot formation and incisor morphogenesis, demonstrate a critical role for
Alx1
in maintaining odontogenic signaling during early tooth development, and provide new mechanistic insight into the dental abnormalities associated with
ALX1
deficiency.