Neural crest cell-derived DKK1 and NEDD4 modulate Wnt signalling in the second heart field to orchestrate outflow tract development
Year: 2026
Type: article
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.
Source: Nature Communications
Authors: Sophie Wiszniak, Dimuthu Alankarage, Iman Lohraseb, Ceilidh Marchant, Genevieve Secker, Deepti Domingo, Jasmine Hartmann, Tianyang Zhang, Wendy Parker, John Toubia, Melissa White, Sandra Piltz, Markus Tondl, Eleni Giannoulatou, David Winlaw, Gillian M. Blue, Congenital Heart Disease Synergy Group, Edwin Kirk, Gavin Chapman, Natasha Nassar, Gary Sholler, Samantha Lain, Patrick P. L. Tam, Paul Thomas, Natasha Harvey, Sally L. Dunwoodie, Quenten Schwarz
Institutions: South Australia Pathology, University of South Australia, Centre for Cancer Biology, Adelaide University, The University of Adelaide, Victor Chang Cardiac Research Institute, UNSW Sydney, Australian Cancer Research Foundation, South Australian Health and Medical Research Institute, SA Genome Editing Facility, Northwestern University, Lurie Children's Hospital, The University of Sydney, Children's Hospital at Westmead, Sydney Children's Hospital, Sydney Children’s Hospitals Network, NSW Health Pathology, Children's Medical Research Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7125394713