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Development 2021 Jan 19;1482:. doi: 10.1242/dev.184341.
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The RNA helicase DDX3 induces neural crest by promoting AKT activity.

Perfetto M , Xu X , Lu C , Shi Y , Yousaf N , Li J , Yien YY , Wei S .

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 GSK3β, leading to reduced levels of β-catenin and Snai1: two GSK3β 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.

PubMed ID: 33318149
PMC ID: PMC7847268
Article link: Development
Grant support: [+]

Species referenced: Xenopus tropicalis
Genes referenced: ctnnb1 ddx3x gapdh gbx2 gbx2.2 msx1 npb pax3 rac1 snai1 snai2 sox9 zfpm1 zic1
Morpholinos: ddx3x MO1 ddx3x MO2

Disease Ontology terms: syndromic intellectual disability
Phenotypes: Xtr Wt + AKTi (Fig.4.A) [+]

Article Images: [+] show captions
References [+] :
Akgumus, Overgrowth Syndromes Caused by Somatic Variants in the Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Pathway. 2017, Pubmed