The RNA helicase DDX3 induces neural crest by promoting AKT activity

Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many individuals carrying DDX3 mutations have additional defects in craniofacial structures and other tissues containing neural crest (NC)-derived cells, we hypothesized that DDX3 is also important for NC development. Using Xenopus tropicalis as a model, we show that DDX3 is required for normal NC induction and craniofacial morphogenesis by regulating AKT kinase activity. Depletion of DDX3 decreases AKT activity and AKT-dependent inhibitory phosphorylation of GSK3 beta, leading to reduced levels of beta-catenin and Snai1: two GSK3 beta substrates that are crucial for NC induction. DDX3 function in regulating these downstream signaling events during NC induction is likely mediated by RAC1, a small GTPase whose translation depends on the RNA helicase activity of DDX3. These results suggest an evolutionarily conserved role of DDX3 in NC development by promoting AKT activity, and provide a potential mechanism for the NC-related birth defects displayed by individuals harboring mutations in DDX3 and its downstream effectors in this signaling cascade.

Automated summary

Mutations in the DDX3 gene may cause intellectual disabilities in humans, affecting neural crest development and craniofacial morphogenesis by regulating AKT kinase activity. This suggests a conserved role of DDX3 in neural crest development and provides insights into potential mechanisms for birth defects associated with DDX3 mutations.