Toddler: An Embryonic Signal That Promotes Cell Movement via Apelin Receptors

TLDR

Most early developmental signals are assumed to have been identified. Toddler induces internalization of APJ/Apelin receptors, and activating APJ/Apelin signaling rescues toddler mutants. We identified Toddler as a conserved peptide that, when absent or overproduced, impairs mesendodermal cell movement, but when locally or ubiquitously expressed promotes gastrulation movements by acting as a motogen through APJ/Apelin signaling, making it the first of potentially many uncharacterized developmental signals.

Abstract

It has been assumed that most, if not all, signals regulating early development have been identified. Contrary to this expectation, we identified 28 candidate signaling proteins expressed during zebrafish embryogenesis, including Toddler, a short, conserved, and secreted peptide. Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation. Local and ubiquitous production of Toddler promote cell movement, suggesting that Toddler is neither an attractant nor a repellent but acts globally as a motogen. Toddler drives internalization of G protein–coupled APJ/Apelin receptors, and activation of APJ/Apelin signaling rescues toddler mutants. These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals.