Bmp16 Regulates Arterial Valve Morphogenesis Through Modulation of Notch Signaling in Zebrafish

Congenital valve defects account for a substantial proportion of cardiovascular malformations, yet the molecular mechanisms orchestrating cardiac valve development remain incompletely elucidated. While Bone morphogenetic protein (BMP) signaling is essential for valvulogenesis, the specific contributions of individual BMP ligands, particularly the teleost-specificbmp16, have not been characterized. Using the CRISPR/Cas9 system, we generated abmp16null knockout and delineated critical roles of this ligand in valvular morphogenesis.bmp16knockout embryos display a significant reduction in Sox9-positive valvular cells and exhibit severely dysplastic arterial valves, characterized by increased interleaflet distance, thickened leaflets, and shortened leaflet lengths. These morphological abnormalities correlate with impaired valve function, culminating in progressive blood regurgitation, ventricular dilation, and pericardial edema. Mechanistically, loss ofbmp16or pharmacological inhibition of BMP signaling significantly downregulatesnotch1bexpression in developing valves, while pharmacological activation of Notch signaling rescues the regurgitation phenotype inbmp16mutants. Collectively, our findings establishbmp16as a novel regulator of valve development and uncover a functional BMP-Notch signaling axis required for vertebrate valvulogenesis, providing new insights into the molecular mechanisms that govern cardiac valve formation and pathogenesis.