Craniofacial anomalies (CFA) are the most frequently occurred congenital disease that affect the growth of the head and facial bones, accounting for about one-third of all human congenital defects. CFAs seem to arise from a combination of genetic factors and environmental influences. Multiple genes mutated in children with CFAs have been identified, and most of which are members of transcription factors family (e.g., Hox, Msx, Dlx, Gsc). However, the pathophysiological mechanisms that governing craniofacial development is far from completed and the gene defects of the majority of CFAs, around 100, have not been thoroughly investigated.
Previous study revealed that the WWP2 E3 ubiquitin ligase facilitates craniofacial development in part through mono-ubiquitination and activation of the pair-like homeobox transcription factor, Goosecoid (Nature Cell Biology, 2011). In the current study, under the supervision of Prof. ZOU Weiguo in Institute of Biochemistry and Cell Biology (SIBCB), Institutions of Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences(CAS) and Prof. WEI Wenyi at Harvard Medical School, SHAO Rui, LIU Jia and colleagues identified that Goosecoid is also likewisely ubiquitinated and activated by the APCCdh1 ubiquitin E3 ligase, leading to transcriptional activation of various Goosecoid target genes crucial for craniofacial development. In keeping with this finding, 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 Goosecoid/Sox6 transcriptional activities. Simultaneously deletion of Cdh1 and Wwp2 results in a more severe craniofacial defect compared with single gene deletion, suggesting a synergistic augment of the Goosecoid activity by these two ubiquitin E3 ligases to orchestrate the ubiquitination of Goosecoid.
These findings revealed a novel role for Cdh1 in craniofacial development through an APC-dependent non-proteolytic ubiquitination and activation of the Goosecoid signaling pathway.
The work entitled “Cdh1 regulates craniofacial development via APCdependent ubiquitination and activation of Goosecoid” was published online in Cell Research on April. 29th, 2016. In this work, researchers from Institute of Biochemistry and Cell Biology (SIBCB), Institutions of Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Harvard Medical School found that ubiquitin E3 ligase Cdh1 regulates craniofacial development via APC-dependent activation of goosecoid.
The work was helped by Dr. WAN Lixin at H. Lee Moffitt Cancer Center and Research Institute and Dr. LIU Jiankang at Xi`an Jiaotong University. Dr. Marcos Malumbres from Centro National de Investigaciones Oncológicas provided Cdh1 conditional knockout mice. The current study was supported by grants from 973 Program [2014CB964704 and 2015CB964503], the National Natural Science Foundation of China (NSFC) [31371463], and NIH grants.
CONTACT:
ZOU Weiguo Ph.D. Professor
Shanghai Institute of Biochemistry and Cell Biology
Chinese Academy of Sciences
SIBCB Building, Rm 1401
320 YueYang Road, Shanghai 200031, China
Tel: 86-21-54921320
Email: zouwg94@sibcb.ac.cn
Figure 1: a. mCT analysis of skulls derived from 5 week old male mice. Craniofacial anomalies in Wwp2/Cdh1 double heterozygous mice. b. APCCdh1 co-operates with Wwp2 to promote non-proteolytic ubiquitination and activation of Gsc signaling, regulating craniofacial development. (Image provided by Prof. ZOU Weiguo’s lab)
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