During the development of any organism, individual signalling pathways are activated to induce differentiation. The control of these pathways is tightly regulated, and usually involves negative feedback and the use of pathway-specific antagonists. In the 1990s, the gene Sprouty was identified as a novel inhibitor of the fibroblast growth factor (FGF) signalling pathway. Work published in this month's issue of Nature Cell Biology now identifies the molecule Sef (for 'similar expression to fgf genes') as a specific inhibitor of FGF signalling in zebrafish (see figure, in which dark staining represents sef expression).

FGFs are growth factors that control proliferation, differentiation, migration and embryonic patterning. FGF8 has a particular role during the early development of zebrafish embryos — it controls dorsal–ventral patterning. It achieves this through the activation of the Ras/Raf/MEK/mitogen-activated protein kinase (MAPK) pathway, which represses expression of bone morphogenetic protein (BMP).

Both Igor Dawid and colleagues, and Christine Thisse and co-workers used a zebrafish embryo DNA library combined with an in situ hybridization screen to identify Sef as a novel modulator of FGF signal transduction. Sef encodes a transmembrane protein with homologues in other species, and it seems to have a conserved tyrosine phosphorylation domain. This conserved tyrosine could be a functional residue that is necessary for transducing signals downstream of activated Sef, although the precise role of this conserved sequence is unknown.

The expression of Sef is positively regulated by FGF8 — overexpression of FGF8 in injected embryos leads to an expansion of the sef expression domain, whereas acerebellar mutants (which lack FGF8 function) or embryos overexpressing a dominant-negative form of the FGF receptor have reduced sef expression.

When both groups ectopically expressed sef, the zebrafish embryos lacked dorsal polarity (similar to the phenotype induced by expression of a dominant-negative FGF receptor), indicating that Sef can inhibit FGF signalling. Morpholino antisense-oligonucleotides to Sef generated embryos that looked similar to the dorsalized phenotypes induced by ectopic FGF8 expression, again suggesting that Sef acts as an antagonist to FGF signalling.

Thisse and colleagues then showed that Sef expression does disrupt the MAPK signalling pathway. In addition, Dawid and colleagues co-immunoprecipitated the FGF receptor with Sef — an interaction that required the intracellular domain of Sef (which contains the conserved tyrosine residue). Although the precise mechanism of Sef action is, as yet, unclear, these two studies have identified a new antagonist of the FGF signalling pathway.