Craniofacial anomalies (CFAs) are the most frequently occurring human congenital disease, and a major cause of infant mortality and childhood morbidity. Although CFAs seems to arise from a combination of genetic factors and environmental influences, the underlying gene defects and pathophysiological mechanisms for most CFAs are currently unknown. Here we reveal a role for the E3 ubiquitin ligase Wwp2 in regulating craniofacial patterning. Mice deficient in Wwp2 develop malformations of the craniofacial region. Wwp2 is present in cartilage where its expression is controlled by Sox9. Our studies demonstrate that Wwp2 influences craniofacial patterning through its interactions with Goosecoid (Gsc), a paired-like homeobox transcription factor that has an important role in craniofacial development. We show that Wwp2-associated Gsc is a transcriptional activator of the key cartilage regulatory protein Sox6. Wwp2 interacts with Gsc to facilitate its mono-ubiquitylation, a post-translational modification required for optimal transcriptional activation of Gsc. Our results identify for the first time a physiological pathway regulated by Wwp2 in vivo, and also a unique non-proteolytic mechanism through which Wwp2 controls craniofacial development.
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The authors thank Dong-Er Zhang, Wei Gu, Tatsuya Kobayashi, Nakamura Yukio and Jian Xu for providing reagents. We also thank Marc Wein for thoughtful comments on the manuscript. The study was supported by NIH grants HD055601 (L.H.G.), K99AR055668 (D.J.) and a grant from Merck Pharmaceuticals. W.G.Z. is a Yerby Fellow at the Harvard School of Public Health.
L.H.G. holds equity in and is on the corporate board of directors of Bristol-Myers Squibb.
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Zou, W., Chen, X., Shim, J. et al. The E3 ubiquitin ligase Wwp2 regulates craniofacial development through mono-ubiquitylation of Goosecoid. Nat Cell Biol 13, 59–65 (2011). https://doi.org/10.1038/ncb2134
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