The RNA helicase DDX3 induces neural crest by promoting AKT activity

• DOI: 10.1242/dev.184341
• Publication Date: 2020-12-16T22:08:42Z
• Authors: Mark Perfetto; Xiaolu Xu; Congyu Lu; Yu Shi; Natasha Yousaf; Jiejing Li; Yvette Y. Yien; Shuo Wei
• Keywords: rac1 GTP-Binding Protein; 0301 basic medicine; Embryo, Nonmammalian; Glycogen Synthase Kinase 3 beta; Protein Stability; Xenopus; Skull; Gene Expression Regulation, Developmental; Xenopus Proteins; DEAD-box RNA Helicases; 03 medical and health sciences; Cartilage; Neural Crest; Face; Morphogenesis; Animals; Snail Family Transcription Factors; Phosphorylation; Proto-Oncogene Proteins c-akt; Wnt Signaling Pathway; beta Catenin

Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many patients 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 GSK3β, leading to reduced levels of β-catenin and Snai1, two GSK3β substrates that are critical 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 patients harboring mutations in DDX3 and its downstream effectors in this signaling cascade.