Clefts of the palate and/or lip are the most common among 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 first 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 is 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 such a functional upstream molecular relationship can be exploited for the development of therapies for human cleft palates that arise from single gene disorders.
Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero
Currently Viewing Accepted Manuscript - Newer Version Available
Shihai Jia, Jing Zhou, Christopher Fanelli, Yinshen Wee, John Bonds, Pascal Schneider, Gabriele Mues, Rena N. D'Souza; Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero. Development 2017; dev.157750. doi: https://doi.org/10.1242/dev.157750
Download citation file:
Advertisement
Call for papers: Uncovering Developmental Diversity
Development invites you to submit your latest research to our upcoming special issue: Uncovering Developmental Diversity. This issue will be coordinated by our academic Editor Cassandra Extavour (Harvard University, USA) alongside two Guest Editors: Liam Dolan (Gregor Mendel Institute of Molecular Plant Biology, Austria) and Karen Sears (University of California Los Angeles, USA).
Choose Development in 2024
In this Editorial, Development Editor-in-Chief James Briscoe and Executive Editor Katherine Brown explain how you support your community by publishing in Development and how the journal champions serious science, community connections and progressive publishing.
Journal Meeting: From Stem Cells to Human Development
Register now for the 2024 Development Journal Meeting From Stem Cells to Human Development. Early-bird registration deadline: 3 May. Abstract submission deadline: 21 June.
Pluripotency of a founding field: rebranding developmental biology
This collaborative Perspective, the result of a workshop held in 2023, proposes a set of community actions to increase the visibility of the developmental biology field. The authors make recommendations for new funding streams, frameworks for collaborations and mechanisms by which members of the community can promote themselves and their research.
Read & Publish Open Access publishing: what authors say
We have had great feedback from authors who have benefitted from our Read & Publish agreement with their institution and have been able to publish Open Access with us without paying an APC. Read what they had to say.