The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development

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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.

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Ashish R Deshwar

Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
Serene C Chng

Institute of Medical Biology, A*STAR, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.
Lena Ho

Institute of Medical Biology, A*STAR, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.
Bruno Reversade

Institute of Medical Biology, A*STAR, Sinagapore, Singapore

Competing interests
The authors declare that no competing interests exist.
Ian C Scott

Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Canada

For correspondence
ian.scott@sickkids.ca

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: Zebrafish were housed and handled as per Canadian Council on Animal Care and Hospital for Sick Children Laboratory Animal Services (LAS) guidelines under LAS protocol number 33584.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.