The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development
Ashish R Deshwar,
Serene C Chng,
Lena Ho,
Bruno Reversade,
Ian C Scott
Affiliations
Ashish R Deshwar
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada
Serene C Chng
Institute of Medical Biology, A*STAR, Singapore, Singapore
Lena Ho
Institute of Medical Biology, A*STAR, Singapore, Singapore
Institute of Medical Biology, A*STAR, Singapore, Singapore; Institute of Molecular and Cellular Biology, A*STAR, Singapore, Singapore; Department of Paediatrics, School of Medicine, National University of Singapore, Singapore
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada; Heart and Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Canada
The Apelin receptor (Aplnr) is essential for heart development, controlling the early migration of cardiac progenitors. Here we demonstrate that in zebrafish Aplnr modulates Nodal/TGFβ signaling, a key pathway essential for mesendoderm induction and migration. Loss of Aplnr function leads to a reduction in Nodal target gene expression whereas activation of Aplnr by a non-peptide agonist increases the expression of these same targets. Furthermore, loss of Aplnr results in a delay in the expression of the cardiogenic transcription factors mespaa/ab. Elevating Nodal levels in aplnra/b morphant and double mutant embryos is sufficient to rescue cardiac differentiation defects. We demonstrate that loss of Aplnr attenuates the activity of a point source of Nodal ligands Squint and Cyclops in a non-cell autonomous manner. Our results favour a model in which Aplnr is required to fine-tune Nodal output, acting as a specific rheostat for the Nodal/TGFβ pathway during the earliest stages of cardiogenesis.
