Neural crest cell-derived DKK1 and NEDD4 modulate Wnt signalling in the second heart field to orchestrate outflow tract development
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.
Authors
- Ceilidh Marchant (ORCID: https://orcid.org/0000-0001-6615-8669)
- Gillian Margaret. Blue
- Deepti Domingo (ORCID: https://orcid.org/0000-0002-7706-872X)
- Dimuthu Alankarage (ORCID: https://orcid.org/0000-0003-2056-2820)
- Iman Lohraseb
- Genevieve A. Secker (ORCID: https://orcid.org/0000-0002-5109-3222)
- Quenten Schwarz (ORCID: https://orcid.org/0000-0002-5958-4181)
- Sandra Piltz (ORCID: https://orcid.org/0000-0003-3386-8140)
- John Toubia (ORCID: https://orcid.org/0000-0002-5135-6504)
- Sophie Wiszniak (ORCID: https://orcid.org/0000-0001-8666-9300)
- Gavin Chapman (ORCID: https://orcid.org/0000-0002-3513-723X)
- Natasha L. Harvey (ORCID: https://orcid.org/0000-0001-9839-8966)
- Melissa White (ORCID: https://orcid.org/0000-0002-8748-9210)
- David Winlaw
- Wendy L. Parker
- Edwin Kirk
- Natasha Nassar
- Gary Sholler
- Sally L. Dunwoodie
- Paul Thomas
- Eleni Giannoulatou
- Jasmine Hartmann
- Markus Tondl
- Tianyang Zhang
- Samantha Lain
Institutions
- South Australia Pathology (AU)
- Northwestern University (US)
- The University of Sydney (AU)
- Children's Medical Research Institute (AU)
- University of South Australia (AU)
- Victor Chang Cardiac Research Institute (AU)
- Australian Cancer Research Foundation (AU)
- Children's Hospital at Westmead (AU)
- UNSW Sydney (AU)
- SA Health (AU)
- Sydney Children's Hospital (AU)
- Lurie Children's Hospital (US)
- South Australian Health and Medical Research Institute (AU)
- Centre for Cancer Biology (AU)
- The University of Adelaide (AU)
- Neuroscience Research Australia (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-22
- DOI
- https://doi.org/10.1038/s41467-026-68459-4
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 0.00