Deshwar Ashish R, Chng Serene C, Ho Lena, Reversade Bruno, Scott Ian C
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Elife. 2016 Apr 14;5:e13758. doi: 10.7554/eLife.13758.
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.
阿片样物质释放肽受体（Aplnr）对于心脏发育至关重要，它控制着心脏祖细胞的早期迁移。在此我们证明，在斑马鱼中，Aplnr调节Nodal/TGFβ信号通路，这是中内胚层诱导和迁移所必需的关键信号通路。Aplnr功能丧失导致Nodal靶基因表达减少，而非肽激动剂激活Aplnr则会增加这些相同靶标的表达。此外，Aplnr缺失导致心脏发生转录因子mespaa/ab的表达延迟。在aplnra/b morphant和双突变胚胎中提高Nodal水平足以挽救心脏分化缺陷。我们证明，Aplnr的缺失以非细胞自主方式减弱了Nodal配体Squint和Cyclops点源的活性。我们的结果支持这样一种模型，即Aplnr是微调Nodal输出所必需的，在心脏发生的最早阶段作为Nodal/TGFβ信号通路的特定变阻器发挥作用。
