Journal
DEVELOPMENT
Volume 148, Issue 2, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.184341
Keywords
DDX3; Neural crest (NC); AKT; GSK3 beta; Wnt signaling; Xenopus
Categories
Funding
- National Institutes of Health [R01GM114105, R01DE029802, P20GM104316, R35GM133560, P01HL032262]
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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.
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.
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