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

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Molecular Genetics

Background:

• Congenital heart valve defects are common cardiovascular malformations.
• Bone morphogenetic protein (BMP) signaling is vital for heart valve development (valvulogenesis).
• The specific roles of individual BMP ligands, like the teleost-specific BMP16, are largely unknown.

Purpose of the Study:

• To investigate the function of the BMP16 ligand in cardiac valve development.
• To elucidate the molecular mechanisms underlying BMP16's role in valvulogenesis.

Main Methods:

• Generated a Bmp16 knockout zebrafish model using CRISPR/Cas9 gene editing.
• Analyzed valvular cell populations (Sox9-positive cells) and valve morphology in Bmp16 knockout embryos.
• Assessed valve function, including blood regurgitation and cardiac morphology.
• Investigated the interplay between BMP and Notch signaling pathways.

Main Results:

• Bmp16 knockout embryos showed reduced Sox9-positive valvular cells and severely dysplastic arterial valves.
• Morphological defects included increased interleaflet distance, thickened, and shortened leaflets, leading to impaired valve function.
• Loss of Bmp16 or BMP inhibition downregulated Notch1b expression in developing valves.
• Notch signaling activation rescued the regurgitation phenotype in Bmp16 mutants.

Conclusions:

• BMP16 is a novel and critical regulator of cardiac valve development.
• A functional BMP-Notch signaling axis is essential for vertebrate valvulogenesis.
• These findings provide new molecular insights into cardiac valve formation and the pathogenesis of congenital valve defects.