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(l to r) Alex Schier, Andi Pauli, Megan Norris, Eivind Valen,  and Guo-Liang Chew

According to the British embryologist Lewis Wolpert, “it is not birth, marriage, or death, but gastrulation which is truly the most important time in your life”. During this process, complex cell rearrangements result in the formation of the three germ layers: ectoderm on the outside and mesoderm and endoderm on the inside. It has been largely mysterious how cell migration during gastrulation is controlled but Andi Pauli and colleagues in the Schier, Joung and Saghatelian labs now describe a previously uncharacterized signal, Toddler, that is essential for normal gastrulation movements (Pauli et al., Science 2014).
The Schier lab discovered Toddler in an effort to distinguish coding from non-coding RNAs. Using evolutionary conservation and mapping of RNA sequences that are translated, Guo-Liang Chew, Eivind Valen, Andi Pauli and colleagues had previously found that many putative non-coding RNAs strongly resemble coding mRNAs (Pauli et al., Genome Research 2011; Chew et al., Development 2013). In an extension of this work, the Schier lab now reports the identification of more than 300 zebrafish proteins that had not been annotated, including more than 20 candidate signaling proteins.
Using Toddler as a test case to determine if any of these candidate signals may have a function, Andi Pauli generated toddler mutant zebrafish and, together with Megan Norris, discovered that this short, conserved secreted peptide is essential for embryogenesis by promoting normal gastrulation movements. Without Toddler, cells are slow to internalize and migrate sluggishly. As one consequence, toddler mutants have no or small hearts.
How does Toddler regulate cell movements? Small peptides often signal through G-protein coupled receptors. Indeed, Toddler was found to activate the Apelin GPCR, and lack of this GPCR leads to very similar phenotypes as seen in toddler mutants. Most motility cues are expressed in specific regions of the embryo and attract or repel cells. Not so Toddler: it is expressed broadly and seems to function as a motogen, a signal that promotes the movement but not the directionality of Apelin receptor expressing cells.
The discovery of Toddler might also address a mystery the Schier lab had tried to solve, with little success, for many years: how does Nodal signaling make cells move? Nodal signaling induces mesodermal and endodermal cell types but it has been unclear how it activates the internalization and movement of these cells. It now seems that Nodal signaling induces the expression of the Toddler receptors in mesodermal and endodermal cells, thus allowing them to initiate gastrulation movements in response to Toddler.
The discovery of Toddler does not only identify a GPCR agonist and promoter of cell movement, it also raises the possibility that several other signaling proteins remain to be characterized. It has been thought that most if not all embryonic signals are known, but the identification of more than 20 candidate signals suggests that Toddler might just be the first in a series of novel developmental signals.
Pauli, A., Valen, E., Lin, M.F., Garber, M., Vastenhouw, N.L., Levin, J.Z., Fan, L., Sandelin, A., Rinn, J.L., Regev, A., and Schier, A.F. (2012) Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. Genome Research 22, 577-91. Epub 2011 Nov 22. Read more in Genome Research or download PDF
Chew, G.-L., Pauli,  A., Rinn, J.L., Regev, A., Schier, A.F., and Valen, E. (2013). Ribosome profiling reveals resemblance between long non-coding RNAs and 5’ leaders of coding RNAs. Development 140, 2828-34. Read more in Development or download PDF

Pauli, A., Norris, M.L., Valen, E., Chew, G.-L., Gagnon, J.A., Zimmerman, S., Mitchell, A., Ma, J., Dubrulle, J., Reyon, D., Tsai, S.Q., Joung, J.K., Saghatelian, A., and Schier, A.F. (2014). Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science (AOP) Read more in Science or download PDF

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