title: The E3 ubiquitin ligase Wwp2 regulates craniofacial development through mono-ubiquitylation of Goosecoid.
abstract: 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.
authors.affiliation: Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, Massachusetts 0211, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zou
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Shim
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Huang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Brady
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Drapp
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sigrist
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Dallas
authors.initials: D
authors.lastname: Jones
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D019465:Craniofacial Abnormalities / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051956:Goosecoid Protein / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055755:SOXD Transcription Factors / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012886:Skull / Q000002:abnormalities / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051956:Goosecoid Protein; C497993:Gsc protein, mouse; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse; C487995:Wwp2 protein, mouse; D044767:Ubiquitin-Protein Ligases