# Neural crest cell-derived DKK1 and NEDD4 modulate Wnt signalling in the second heart field to orchestrate outflow tract development

## TL;DR

This study reveals how neural crest cells regulate heart development by modulating Wnt signaling, uncovering a new pathway linked to congenital heart disease.

## Contribution

The study identifies DKK1 and NEDD4 as key regulators in neural crest cells that influence heart development and congenital heart disease.

## Key findings

- Neural crest cells are a primary source of DKK1, which modulates Wnt signaling in cardiac progenitors.
- NEDD4 regulates DKK1, and its disruption causes outflow tract defects in the heart.
- A new NEDD4 variant is identified as a causative factor in human congenital heart disease.

## Abstract

Cardiac outflow tract morphogenesis requires coordinated interactions between multiple cell populations and is dependent on the contribution of cardiac progenitors from the second heart field. While neural crest cells have been proposed to impact second heart field development, how they regulate progenitor behaviour remains unclear. Here, we discover neural crest cells are a primary source of Dickkopf-1 (DKK1) which modulates Wnt signalling activity in the second heart field to influence the balance between cardiac progenitor maintenance and differentiation. We show that the ubiquitin ligase NEDD4 regulates DKK1, with disruption of Nedd4 leading to outflow tract defects. We further identify a new NEDD4 variant underlying human congenital heart disease. Our findings uncover an unexpected role for neural crest cells as a rheostat of Wnt signalling in cardiac progenitors, identifying a new molecular pathway promoting outflow tract morphogenesis, and a new causative factor of congenital heart disease.

Neural crest cells have been implicated in heart development, yet the mechanisms by which they act have remained elusive. Here, the authors show neural crest cells modulate Wnt signalling in cardiac progenitors, providing new insight into the mechanisms underpinning congenital heart defects.