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

Ashish R Deshwar,Bruno Reversade,Serene C Chng,Ian C Scott,Lena Ho

doi:10.7554/elife.13758

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.

Highlights

During gastrulation, complex cell movements occur which result in the localization of progenitor populations to discrete embryonic regions for subsequent organogenesis
In order to assess the contribution of aplnra to the process of gastrulation and heart development, we knocked it out using custom TALEN pairs targeted to its unique exon on chromosome 8 (Figure 1A)
In this study we demonstrate that the endoderm and cardiac defects in zebrafish lacking aplnr can be attributed to decreased Nodal signaling

Summary

Introduction

Complex cell movements occur which result in the localization of progenitor populations to discrete embryonic regions for subsequent organogenesis. Loss of Apelin receptor (Aplnr) function in zebrafish, as manifested in the recessive grinch mutant, results in a decrease or absence of cardiogenesis, and affects expression of the earliest known cardiac mesoderm markers (Scott et al, 2007; Zeng et al, 2007). Aplnr ( known as Apj and Agtrl1) is expressed in the gastrulating mesoderm, with Aplnr mutant mice exhibiting incompletely penetrant cardiovascular malformations including thinning of the myocardium, ventricular septation defects, an enlarged right ventricle and improper heart looping (Kang et al, 2013). While a role for Aplnr signaling in the earliest events of cardiac development is evident, how Aplnr functions in this context remains unclear. Aplnr has been implicated in the movement of cardiac progenitors during gastrulation to the anterior lateral plate mesoderm (ALPM), the site of heart development, with a delay in anterior migration of presumed cardiac progenitors during

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