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 <i>Smg5</i> in mouse craniofacial neural crest cells leads to hypoplastic mandibles, subsequently inducing tongue mispositioning and cleft palate formation. Furthermore, <i>Smg5</i> 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 <i>Porcn</i> transcript leads to reduced Porcn protein and impaired Wnt5a/JNK signaling, a crucial pathway for craniofacial morphogenesis. Finally, death of Smg5<i>-</i>deficient craniofacial neural crest cells can be ameliorated by Wnt5a in craniofacial neural crest (CNC) <i>in vitro</i> explants. Taken together, our findings demonstrate that <i>Smg5</i>-mediated NMD regulates mammalian craniofacial development by fine-tuning Wnt signaling through post-transcriptional regulation of <i>Porcn</i>.