Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero

Development. 2017 Oct 15;144(20):3819-3828. doi: 10.1242/dev.157750. Epub 2017 Sep 11.


Clefts of the palate and/or lip are among the most common human craniofacial malformations and involve multiple genetic and environmental factors. Defects can only be corrected surgically and require complex life-long treatments. Our studies utilized the well-characterized Pax9-/- mouse model with a consistent cleft palate phenotype to test small-molecule Wnt agonist therapies. We show that the absence of Pax9 alters the expression of Wnt pathway genes including Dkk1 and Dkk2, proven antagonists of Wnt signaling. The functional interactions between Pax9 and Dkk1 are shown by the genetic rescue of secondary palate clefts in Pax9-/-Dkk1f/+;Wnt1Cre embryos. The controlled intravenous delivery of small-molecule Wnt agonists (Dkk inhibitors) into pregnant Pax9+/- mice restored Wnt signaling and led to the growth and fusion of palatal shelves, as marked by an increase in cell proliferation and osteogenesis in utero, while other organ defects were not corrected. This work underscores the importance of Pax9-dependent Wnt signaling in palatogenesis and suggests that this functional upstream molecular relationship can be exploited for the development of therapies for human cleft palates that arise from single-gene disorders.

Keywords: Cleft palate; Mouse; Palatogenesis; Pax9; Small molecule; Wnt; Wnt agonist.

MeSH terms

  • Animals
  • Body Patterning
  • Cell Proliferation
  • Cleft Palate / genetics*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Intercellular Signaling Peptides and Proteins / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Morphogenesis
  • Osteogenesis
  • PAX9 Transcription Factor
  • Paired Box Transcription Factors / genetics*
  • Palate / embryology*
  • Phenotype
  • Protein Binding
  • Wnt Signaling Pathway
  • Wnt1 Protein / agonists*
  • Wnt1 Protein / genetics*


  • Dkk1 protein, mouse
  • Dkk2 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • PAX9 Transcription Factor
  • Paired Box Transcription Factors
  • Pax9 protein, mouse
  • Wnt1 Protein
  • Wnt1 protein, mouse