Editors' ChoiceDevelopment

Gastrulating Cells Toddle

Sci. Signal.  18 Feb 2014:
Vol. 7, Issue 313, pp. ec46
DOI: 10.1126/scisignal.2005182

The secreted signals and signaling pathways that specify cell fate and pattern the body axes of early vertebrate embryos are generally well characterized, but the signals that trigger gastrulation, a major morphogenetic movement that internalizes the endoderm and mesoderm, remain largely uncharacterized. Pauli et al. identified Toddler (Tdl) as a secreted short peptide that is required for gastrulation in zebrafish embryos. The tdl transcript was present throughout the embryo during late blastula and early gastrula stages and was required only during these stages for proper gastrulation. Loss-of-function mutants had various endodermal and mesodermal defects, and the endodermal cells in these mutants migrated more slowly and shorter distances than endodermal cells in gastrulating wild-type embryos. Injection of 2 pg of tdl mRNA rescued the loss-of-function phenotype, but injection of 10 pg or more partially phenocopied loss-of-function mutations, indicating that the precise amount of Tdl activity was important for proper gastrulation. The Apelin receptor (APJ), a G protein–coupled receptor (GPCR) that is activated by the peptide Apelin, was present in mesendodermal cells, and its abundance peaked during gastrulation. Embryos lacking Apelin receptors phenocopied tdl mutants, and injection of Apelin mRNA, which is not normally present during gastrulation, rescued the tdl mutant phenotype. GPCRs are typically internalized upon activation, and expressing tdl in clones of cells in pregastrula embryos caused internalization of a fluorescently tagged version of the Apelin receptor in neighboring cells. This study identifies Tdl as an endogenous ligand for the Apelin receptor, activation of which is required for proper cell movements during zebrafish gastrulation. Human and mouse homologs of tdl were also identified, suggesting that this peptide may also function as a ligand for Apelin receptors in other species. Tdl (also called Elabela) was recently independently reported by Chng et al. to act as a ligand for the Apelin receptor during heart development in zebrafish.

A. Pauli, M. L. Norris, E. Valen, G.-L. Chew, J. A. Gagnon, S. Zimmerman, A. Mitchell, J. Ma, J. Dubrulle, D. Reyon, S. Q. Tsai, J. K. Joung, A. Saghatelian, A. F. Schier, Toddler: An embryonic signal that promotes cell movement via apelin receptors. Science 343, 1248636 (2014). [Abstract] [Full Text]

S. C. Chng, L. Ho, J. Tian, B. Reversade, ELABELA: A hormone essential for heart development signals via the apelin receptor. Dev. Cell 27, 672–680 (2013). [PubMed]