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Next-Generation Sequencing Facilitates Quantitative Analysis of the Effects of Wnt Agonist Treatments on Palate Formation

ABSTRACT: Nonsyndromic clefts of the palate and/or lip are common birth defects arising in about 1/700 live births worldwide. They are caused by multiple genetic and environmental factors, can only be corrected surgically and require complex post-operative care that imposes significant burdens on individuals and society. Our understanding of the molecular networks that control palatogenesis has advanced through studies on mouse genetic models of cleft palate. In particular, the transcription factor Pax9 regulates palatogenesis through the Bmp, Fgf and Shh pathways in mice. But there is still much to learn about Pax9's relationship with other signaling pathways in this process. Here we show alterations of Wnt expression and decreased Wnt activity in Pax9-/- palatal shelves are a likely result of Pax9's ability to directly bind and repress the promoters of Dkk1 and Dkk2, proteins that antagonize Wnt signaling. We exploited this relationship by delivering small-molecule Dkk inhibitors into the tail-veins of pregnant Pax9+/- females from E10.5 to E14.5. Such therapies restored Wnt signaling, promoted cell proliferation, bone formation and fusion of palatal shelves in Pax9-/- embryos. These data uncover a connection between the roles of Pax9 and Wnt genes in palatogenesis and offer a new approach for treating human cleft palates.

ORGANISM(S): Mus musculus

PROVIDER: GSE101825 | GEO | 2017/10/16

SECONDARY ACCESSION(S): PRJNA395594

REPOSITORIES: GEO

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Project description:We identify a role for two evolutionarily related, secreted metalloproteases of the ADAMTS family (A disintegrin-like and metalloprotease domain with thrombospondin type-1 motif), ADAMTS20 and ADAMTS9, in palatogenesis. Adamts20 mutations cause the mouse white spotting mutant belted (bt), whereas Adamts9 is essential for survival beyond 7.5 days of gestation (E7.5). Functional overlap of Adamts9 with Adamts20 was established in bt/bt:Adamts9+/- mice, which have increased white spotting relative to bt mice, as previously reported, and a fully penetrant cleft palate. Palatal closure was delayed, although eventually completed, in both bt/+;Adamts9+/- and bt/bt mice, demonstrating a cooperative role of these related genes. Adamts9 and Adamts20 are both expressed in palatal mesenchyme, with Adamts9 expressed exclusively in microvascular endothelial cells. Palatal shelves from bt/bt:Adamts9+/- mice fused in culture, suggesting an intact TGF signaling pathway in palatal epithelium, and indicating a temporally specific delay in palatal shelf elevation and growth toward the midline. Palatal shelf mesenchymal cells showed a statistically significant decrease of cell proliferation at E13.5 and E14.5, as well as decreased processing of versican, an ADAMTS substrate, at these stages. Vcan haploinsufficiency led to a greater penetrance of cleft palate in bt mice, and impaired proliferation was also seen in palatal mesenchymal cells of these mice, suggesting a role for ADAMTS-mediated versican proteolysis in palatal closure. In a parallel with recent work identifying a role for a bioactive ADAMTS-generated versican fragment in regulating apoptosis during interdigital web regression, we propose that versican proteolysis may influence palatal mesenchymal cell proliferation. Palatal shelves were dissected from four E13.75 Adamts9+/-:bt/bt embyos (correspond to the 4 samples: Palate_Adamts9+/-:bt/bt_Rep1, Palate_Adamts9+/-:bt/bt_Rep2, Palate_Adamts9+/-:bt/bt_Rep3 and Palate_Adamts9+/-:bt/bt_Rep4) and age-matched 3 wild-type C57Bl/6 embryos (correspond to the 3 samples: Palate_WT_Rep1, Palate_WT_Rep2, and Palate_WT_Rep3) that were used as the controls

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Next-Generation Sequencing Facilitates Quantitative Analysis of the Effects of Wnt Agonist Treatments on Palate Formation

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