Loss of wbp11 Causes Multi-System Developmental Defects: A Zebrafish Model of VACTERL Association

Western blot analysis confirmed that injection of wbp11 morpholino (MO) markedly reduced Wbp11 protein levels, resulted in significantly increased morphological abnormalities, and caused a general delay in embryonic development. Phenotypic characterization demonstrated that wbp11 knockdown leads to multi-system developmental defects, including cardiac malformations, pericardial edema and impaired heart looping; vascular defects, underdeveloped mesenteric vessels and reduced cranial vasculature; spinal curvature and aberrant notochord structure; various fin hypoplasia phenotypes with reduced fin sizes; and transcriptional dysregulation of kidney developmental marker genes.

These phenotypes closely resemble the core clinical features of VACTERL association, demonstrating that loss of Wbp11 can induce multi-system congenital anomalies in a vertebrate model. Transcriptomic and differential alternative splicing analyses, together with molecular biological assessments, further revealed significant dysregulation of genes associated with cardiac function, angiogenesis, skeletal patterning, fin development, and kidney development, thereby providing molecular insights into the observed morphological defects.

Collectively, this study establishes a wbp11-MO mediated knockdown zebrafish model, demonstrates its capacity to partially recapitulate key features of VACTERL association, and provides a powerful platform for dissecting the underlying molecular mechanisms and exploring potential therapeutic interventions for this disorder.