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

## TL;DR

This study shows that Bmp16 is crucial for heart valve development in zebrafish by regulating Notch signaling, offering new insights into congenital valve defects.

## Contribution

The study identifies Bmp16 as a novel regulator of arterial valve morphogenesis through modulation of Notch signaling in zebrafish.

## Key findings

- bmp16 knockout embryos show reduced Sox9-positive valvular cells and dysplastic arterial valves.
- Loss of bmp16 or inhibition of BMP signaling downregulates notch1b in developing valves.
- Notch signaling activation rescues valve defects in bmp16 mutants.

## Abstract

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-specific bmp16, have not been characterized. Using the CRISPR/Cas9 system, we generated a bmp16 null knockout and delineated critical roles of this ligand in valvular morphogenesis. bmp16 knockout 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 of bmp16 or pharmacological inhibition of BMP signaling significantly downregulates notch1b expression in developing valves, while pharmacological activation of Notch signaling rescues the regurgitation phenotype in bmp16 mutants. Collectively, our findings establish bmp16 as 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.