title: Cdh1 regulates craniofacial development via APC-dependent ubiquitination and activation of Goosecoid.
abstract: Craniofacial anomalies (CFAs) characterized by birth defects of skull and facial bones are the most frequent congenital disease. Genomic analysis has identified multiple genes responsible for CFAs; however, the underlying genetic mechanisms for the majority of CFAs remain largely unclear. Our previous study revealed that the Wwp2 E3 ubiquitin ligase facilitates craniofacial development in part through inducing monoubiquitination and activation of the paired-like homeobox transcription factor, Goosecoid (Gsc). Here we report that Gsc is also ubiquitinated and activated by the APC(Cdh1) E3 ubiquitin ligase, leading to transcriptional activation of various Gsc target genes crucial for craniofacial development. Consistenly, neural crest-specific Cdh1-knockout mice display similar bone malformation as Wwp2-deficient mice in the craniofacial region, characterized by a domed skull, a short snout and a twisted nasal bone. Mechanistically, like Wwp2-deficient mice, mice with Cdh1 deficiency in neural crest cells exhibit reduced Gsc/Sox6 transcriptional activities. Simultaneous deletion of Cdh1 and Wwp2 results in a more severe craniofacial defect compared with single gene deletion, suggesting a synergistic augmentation of Gsc activity by these two E3 ubiquitin ligases. Hence, our study reveals a novel role for Cdh1 in craniofacial development through promoting APC-dependent non-proteolytic ubiquitination and activation of Gsc.
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Shao
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.|Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Life Science, FIST, Xi'an Jiaotong University, Xi'an, Shanxi 710049, China.|Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an, Shanxi 710061, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yan
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.|Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.|State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, 17 People's South Road, Chengdu, Sichuan 610041, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Life Science, FIST, Xi'an Jiaotong University, Xi'an, Shanxi 710049, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Cell Division and Cancer Group, Centro National de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.|Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wan
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zou
mesh_terms: D000595:Amino Acid Sequence; D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D064200:Cdh1 Proteins / Q000378:metabolism*; D005145:Face / Q000196:embryology*; D051956:Goosecoid Protein / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D011485:Protein Binding; D055755:SOXD Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000196:embryology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D064200:Cdh1 Proteins; C577585:Fzr1 protein, mouse; D051956:Goosecoid Protein; C497993:Gsc protein, mouse; D055755:SOXD Transcription Factors; C487995:Wwp2 protein, mouse; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases