Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives

Cell Rep. 2017 Aug 29;20(9):2116-2130. doi: 10.1016/j.celrep.2017.08.014.


Apela (also known as Elabela, Ende, and Toddler) is a small signaling peptide that activates the G-protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. Three-dimensional micro-computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. Transcriptomics at late gastrulation identified aberrant upregulation of erythroid and myeloid markers in mutant embryos prior to the appearance of physical malformations. Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos.

Keywords: APJ; Apela; Apelin; Aplnr; Elabela; Ende; Toddler; cardiovascular development; gastrulation; macrophages; micro-computed tomography; microCT; vascular remodeling.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apelin / metabolism
  • Apelin Receptors / metabolism
  • CD11b Antigen / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Embryo Loss / genetics*
  • Embryo Loss / pathology*
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / pathology
  • Embryonic Development
  • Endothelial Cells / metabolism
  • Erythroid Cells / metabolism
  • Gene Expression Regulation, Developmental
  • Mesoderm / embryology*
  • Mesoderm / metabolism*
  • Mice, Knockout
  • Mutation / genetics
  • Myeloid Cells / metabolism
  • Myocardium / pathology
  • Penetrance*
  • Peptide Hormones
  • Peptides / chemistry
  • Peptides / metabolism*
  • Phenotype
  • Signal Transduction
  • Survival Analysis
  • Up-Regulation / genetics
  • Vascular Remodeling


  • Apela protein, mouse
  • Apelin
  • Apelin Receptors
  • CD11b Antigen
  • Carrier Proteins
  • Peptide Hormones
  • Peptides