Fine-tuning of Wnt signaling by RNA surveillance factor Smg5 in the mouse craniofacial development
Shicheng Zhu,
Suman Huo,
Weiran He,
Caiyan Huang,
Jiannan Zhang,
Xiaoning Jiang,
Yeqing Qian,
Chengyan Chen,
Zhong-Min Dai,
Xueqin Yang,
Mengsheng Qiu,
Tangliang Li,
Xiao-Jing Zhu
Affiliations
Shicheng Zhu
College of Life and Environmental Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
Suman Huo
College of Life and Environmental Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
Weiran He
College of Life and Environmental Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
Caiyan Huang
College of Life and Environmental Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
Jiannan Zhang
College of Life and Environmental Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
Xiaoning Jiang
School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
Yeqing Qian
Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
Chengyan Chen
State Key Laboratory of Microbial Technology, Shandong University, Qingdao 250100, China
Zhong-Min Dai
College of Life and Environmental Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
Xueqin Yang
College of Life and Environmental Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
Mengsheng Qiu
College of Life and Environmental Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
Tangliang Li
School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; State Key Laboratory of Microbial Technology, Shandong University, Qingdao 250100, China; Corresponding author
Xiao-Jing Zhu
College of Life and Environmental Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Corresponding author
Summary: The specific roles of nonsense-mediated mRNA decay (NMD), a translation-dependent RNA quality control mechanism that degrades mRNAs containing premature termination codons (PTCs), in mammalian craniofacial development have remained unclear. Here, we show that knockout of the essential NMD factor Smg5 in mouse craniofacial neural crest cells leads to hypoplastic mandibles, subsequently inducing tongue mispositioning and cleft palate formation. Furthermore, Smg5 loss triggers massive cell apoptosis and disrupts cell differentiation, accompanied by widespread alterations in alternative splicing and a surge in PTC-containing mRNA levels. Notably, the abnormal upregulation of a PTC-containing Porcn transcript leads to reduced Porcn protein and impaired Wnt5a/JNK signaling, a crucial pathway for craniofacial morphogenesis. Finally, death of Smg5-deficient craniofacial neural crest cells can be ameliorated by Wnt5a in craniofacial neural crest (CNC) in vitro explants. Taken together, our findings demonstrate that Smg5-mediated NMD regulates mammalian craniofacial development by fine-tuning Wnt signaling through post-transcriptional regulation of Porcn.
