Jia Shihai, Zhou Jing, Fanelli Christopher, Wee Yinshen, Bonds John, Schneider Pascal, Mues Gabriele, D'Souza Rena N
School of Dentistry, University of Utah, Salt Lake City, UT 84112, USA.
Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX 75246, USA.
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 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 and , proven antagonists of Wnt signaling. The functional interactions between Pax9 and Dkk1 are shown by the genetic rescue of secondary palate clefts in embryos. The controlled intravenous delivery of small-molecule Wnt agonists (Dkk inhibitors) into pregnant mice restored Wnt signaling and led to the growth and fusion of palatal shelves, as marked by an increase in cell proliferation and osteogenesis , 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.
腭裂和/或唇裂是人类最常见的颅面畸形之一，涉及多种遗传和环境因素。这些缺陷只能通过手术矫正，并且需要终身进行复杂的治疗。我们的研究利用具有一致腭裂表型的特征明确的小鼠模型来测试小分子Wnt激动剂疗法。我们发现，Pax9的缺失会改变Wnt信号通路基因的表达，包括Dkk1和Dkk2，它们是Wnt信号的已知拮抗剂。Pax9与Dkk1之间的功能相互作用通过在Pax9-/-胚胎中继发性腭裂的基因拯救得以体现。将小分子Wnt激动剂（Dkk抑制剂）通过静脉注射给怀孕的Pax9-/-小鼠，可恢复Wnt信号，并导致腭突的生长和融合，表现为细胞增殖和成骨增加，而其他器官缺陷并未得到纠正。这项工作强调了Pax9依赖的Wnt信号在腭发育中的重要性，并表明这种功能性的上游分子关系可用于开发针对由单基因疾病引起的人类腭裂的治疗方法。
