Fine-tuning of Wnt signaling by RNA surveillance factor Smg5 in the mouse craniofacial development

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.