Cdhl regulates craniofacial development via APC- dependent ubiquitination and activation of Goosecoid  

作　　者：Rui Shao Jia Liu Guang Yan Jinfang Zhang Yujiao Han Jianfeng Guo Zhan Xu Zhu Yuan Jiankang Liu Marcos Malumbres Lixin Wan Wenyi Wei Weiguo Zou 

机构地区：[1]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 [2]Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA [3]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 [4]Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an, Shanxi 710061, China [5]Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China [6]Cell Division and Cancer Group, Centro National de Investigaciones Oncologicas (CNIO), Madrid, Spain [7]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 [8]Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA

出　　处：《Cell Research》2016年第6期699-712,共14页细胞研究（英文版）

基　　金：Acknowledgments We thank Brian North, Shavali Shaik, Aletn W. Lau, Matthew B. Greenblatt, Hiroyuki Inuzuka and Pengda Liu for critical reading of the manuscript, and members of the Zou and Wei labs for useful discussions. This work was supported by the Chinese Ministry of Science and Technology （MOST, 973 Program; 2014CB964704 and 2015CB964503）, the National Natural Science Foundation of China （NSFC; 31371463） and NIH （GM089763, GM094777 and CA177910 to WW）. WZ is a scholar of the ＇National I000 Young Talents Program of China＇ and ＇the National Science Fund for Excellent Young Scholars＇ （NSFC; 81322027）. WW is a Leukemia and Lymphoma Society Scholar and ACS Research Scholar.

摘　　要：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 CFA~ remain largely unclear. Our previous study revealed that the Wwp2 E3 ubiq- uitin ligase facilitates craniofacial de,~elopment in part through inducing monoubiquitination and activation of the paired-like homeobox transcription factor, Gooseeoid （Gsc）. Here we report that Gse is also ubiquitinated and acti- vated by the APCcdhl E3 ubiquitin ligase, leading to transcriptional activation of various Gse target genes crucial for craniofacial development. Consisteni3; neural crest-specific Cdhl-knockout mice display similar bone malformation as Wwp2-deficient mice in the eraniofacial region, characterized by a domed skull, a short snout and a twisted nasal bone. Mechanistically, like Wwp2-defi,：ient mice, mice with Cdhl deficiency in neural crest cells exhibit reduced Gsc/ Sox6 transcriptional activities. Simultaneous deletion of Cdhl 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 Cdhl in craniofaeial development through promoting APC-depen- dent non-proteolytie ubiquitination and activation of Gse.

关 键 词：APC Cdhl Wwp2 GOOSECOID Sox6 craniofacial development craniofacial anomalies 

分 类 号：Q51[生物学—生物化学] Q26