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

Details

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Version: Final published version
Serval ID
serval:BIB_7CFF3D74681E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero.
Journal
Development
Author(s)
Jia S., Zhou J., Fanelli C., Wee Y., Bonds J., Schneider P., Mues G., D'Souza R.N.
ISSN
1477-9129 (Electronic)
ISSN-L
0950-1991
Publication state
Published
Issued date
2017
Peer-reviewed
Oui
Volume
144
Number
20
Pages
3819-3828
Language
english
Abstract
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(-/-)Dkk1(f/+);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
Pubmed
Web of science
Open Access
Yes
Create date
06/11/2017 18:30
Last modification date
20/08/2019 14:38
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