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

• Published in: 细胞研究：英文版 2016 (6), p.699-712
• Main Author: 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
• Format: Article
• Language: English
• Subjects: APC; 出生缺陷; 发育; 基因组分析; 泛素化; 泛素连接酶; 转录因子; 转录激活
• ISSN: 1001-0602; 1748-7838

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.