Deficiency of <i>DDX3X</i> results in neurogenesis defects and abnormal behaviors via dysfunction of the Notch signaling.

Abstract

The molecular mechanisms underlying the neurodevelopmental disorders (NDDs) caused by <i>DDX3X</i> variants remain poorly understood. In this study, we validated that de novo <i>DDX3X</i> variants are enriched in female developmental delay (DD) patients and mainly affect the evolutionarily conserved amino acids based on a meta-analysis of 46,612 NDD trios. We generated a <i>ddx3x</i> deficient zebrafish allele, which exhibited reduced survival rate, DD, microcephaly, adaptation defects, anxiolytic behaviors, social interaction deficits, and impaired spatial recognitive memory. As revealed by single-nucleus RNA sequencing and biological validations, <i>ddx3x</i> deficiency leads to reduced neural stem cell pool, decreased total neuron number, and imbalanced differentiation of excitatory and inhibitory neurons, which are responsible for the behavioral defects. Indeed, the supplementation of L-glutamate or glutamate receptor agonist ly404039 could partly rescue the adaptation and social deficits. Mechanistically, we reveal that the <i>ddx3x</i> deficiency attenuates the stability of the <i>crebbp</i> mRNA, which in turn causes downregulation of Notch signaling and defects in neurogenesis. Our study sheds light on the molecular pathology underlying the abnormal neurodevelopment and behavior of NDD patients with <i>DDX3X</i> mutations, as well as providing potential therapeutic targets for the precision treatment.