FIGURE 10

ddx3xa Governs Cardiac Morphogenesis Through Wnt/β-Catenin Signaling. Schematic diagram illustrating the mechanistic role of ddx3xa in zebrafish cardiac development. CRISPR/Cas9-mediated ddx3xa knockout results in developmental defects including developmental delay, trunk malformations, and cardiac abnormalities characterized by pericardial edema and impaired looping. Transcriptomic profiling of ddx3xa^−/− mutants at 72 hpf identifies dysregulation of key cardiac developmental genes (bmp4, actn2b, tbx5, nppb) and reveals hyperactivation of the Wnt/β-catenin pathway. Mechanistically, ddx3xa deficiency upregulates the transcription factor Tcf/Lef1, leading to aberrant expression of its downstream targets bmp4 and tbx5. Pharmacological inhibition of Wnt signaling with IWR-1 normalizes the expression of these cardiac genes and partially rescues the morphological defects. This work establishes ddx3xa as a critical regulator of cardiac development through modulation of the Wnt/β-catenin pathway, providing novel mechanistic insights into the cardiac comorbidities of DDX3X syndrome and highlighting the therapeutic potential of Wnt pathway modulation.