Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling

Elife. 2017 Nov 9:6:e22626. doi: 10.7554/eLife.22626.


Toddler/Apela/Elabela is a conserved secreted peptide that regulates mesendoderm development during zebrafish gastrulation. Two non-exclusive models have been proposed to explain Toddler function. The 'specification model' postulates that Toddler signaling enhances Nodal signaling to properly specify endoderm, whereas the 'migration model' posits that Toddler signaling regulates mesendodermal cell migration downstream of Nodal signaling. Here, we test key predictions of both models. We find that in toddler mutants Nodal signaling is initially normal and increasing endoderm specification does not rescue mesendodermal cell migration. Mesodermal cell migration defects in toddler mutants result from a decrease in animal pole-directed migration and are independent of endoderm. Conversely, endodermal cell migration defects are dependent on a Cxcr4a-regulated tether of the endoderm to mesoderm. These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling.

Keywords: Apela; Cxcr4a; Elabela; Gastrulation; Nodal; Toddler; developmental biology; stem cells; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Movement*
  • Gene Knockout Techniques
  • Mesoderm / embryology*
  • Nodal Signaling Ligands / metabolism*
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction*
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • CXCR4a protein, zebrafish
  • Nodal Signaling Ligands
  • Receptors, CXCR4
  • Zebrafish Proteins
  • toddler peptide, zebrafish