title: The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development.
abstract: 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.
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Deshwar
authors.affiliation: Institute of Medical Biology, A*STAR, Singapore, Singapore.
authors.forename: Serene C
authors.initials: SC
authors.lastname: Chng
authors.affiliation: Institute of Medical Biology, A*STAR, Singapore, Singapore.
authors.forename: Lena
authors.initials: L
authors.lastname: Ho
authors.affiliation: 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.
authors.forename: Bruno
authors.identifier: 0000-0002-4070-7997
authors.initials: B
authors.lastname: Reversade
authors.affiliation: 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.
authors.forename: Ian C
authors.identifier: 0000-0001-6665-1410
authors.initials: IC
authors.lastname: Scott
mesh_terms: D000818:Animals; D000075244:Apelin Receptors; D006321:Heart / Q000196:embryology*; D055457:Nodal Protein / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D000075244:Apelin Receptors; D055457:Nodal Protein; D043562:Receptors, G-Protein-Coupled; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; C519093:apelin receptor, zebrafish
keywords: Aplnr; Nodal; cardiac progenitors; developmental biology; heart development; mesendoderm; stem cells; zebrafish