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bioRxiv · 10.1101/110692

The Pax9/Wnt pathway regulates secondary palate formation in mice

Jia, S.·Zhou, J.·Fanelli, C.·Wee, Y.·Bonds, J.·Schneider, P.·Mues, G.·D'Souza, R. N.
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Abstract

Clefts of the palate and/or lip arise in about 1/700 human live births and are caused by multiple genetic and environmental factors. Studies of mouse knockout models of cleft palate have improved our understanding of the molecular control of palatogenesis. While it is known that Pax9 regulates palatogenesis through Bmp, Fgf and Shh signaling, there is still much to learn about its precise relationship with other pathways. Here we show that alterations of Wnt expression and decreased Wnt activity in Pax9-/- palatal shelves are a result of Pax9s ability to directly bind and repress the promoters of Dkk1 and Dkk2, proteins that antagonize Wnt signaling. The delivery of small-molecule Dkk inhibitors (Wnt agonists) into the tail-veins of pregnant Pax9+/- mice from E10.5 to E14.5 restored Wnt signaling, promoted cell proliferation, bone formation and restored the fusion of palatal shelves in Pax9-/- embryos. In contrast, other organ defects in Pax9 mutants were not corrected. These data uncover a unique molecular relationship between Pax9 and Wnt genes in palatogenesis and offer a new approach for treating cleft palates in humans.\n\nSummary StatementThese studies demonstrate that the Pax9/Wnt genes regulate murine palatogenesis. This unique molecular relationship is proven by the correction of cleft defects in Pax9-deficient mice through Wnt agonist therapies.

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Jia, S., Zhou, J., Fanelli, C., Wee, Y., Bonds, J., Schneider, P., Mues, G., D'Souza, R. N.. 2017-02-22. The Pax9/Wnt pathway regulates secondary palate formation in mice. https://doi.org/10.1101/110692

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