During organogenesis, inductive signals by several well-characterized signalling molecules, such as Hedgehog and Wingless, generate clusters of visceral-mesoderm precursors. The secreted protein Jelly belly (Jeb) is essential for visceral-mesoderm development during Drosophila melanogaster embryogenesis. It is taken up by visceral-mesoderm precursors, but the consequential signalling events during muscle development have not been defined. Now, though, two papers in Nature — by Lee et al. and Englund et al. — report the identification of a receptor and a signalling pathway downstream of Jeb.

Visceral-mesoderm precursors comprise muscle founders and fusion-competent myoblasts. Founder cells, which recruit fusion-competent myoblasts, express the myoblast fusion gene dumbfounded ( duf ) and the T-box gene org-1 ; and fusion-competent cells express another fusion gene, Sticks and stones ( sns ). Lee et al. showed that overexpressing Jeb activates duf and org-1, and downregulates sns, which indicates a potential role for Jeb in specifying founder cells. In jeb-mutant embryos, no visceral founders were specified.

Because the extracellular signal-regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) pathway is required in the somatic-muscle lineage for specifying founder cells, Lee et al. investigated this signalling pathway in the visceral mesoderm. Both Lee et al. and Englund et al. found ERK/MAPK to be activated in visceral-mesoderm precursors. Indeed, activated ERK/MAPK was absent in jeb mutants. On this basis, activation of ERK/MAPK should rescue jeb mutants — which it did.

So how does Jeb signal to ERK/MAPK? The receptor tyrosine kinase Alk was expressed in the early visceral mesoderm in cells directly adjacent to somatic mesoderm cells that were expressing jeb. Furthermore, activated ERK/MAPK was detected in cells that expressed Alk and that had taken up Jeb. These observations hinted that Alk was the Jeb receptor. Both groups saw that, in the absence of Alk, embryos resembled jeb-mutant embryos. Furthermore, ectopic expression of Alk — in particular, using a constitutively active version that resembles the human ALK oncogene (which contributes to non-Hodgkin's lymphoma) — rescued the phenotype of jeb mutants. Both groups then showed that, in the absence of Alk activity and in jeb-mutant embryos, duf was no longer expressed in muscle-founder cells.

Englund et al. reported that Jeb and Alk co-immunoprecipitated, and that this was dependent on the extracellular domain of Alk. Further biochemical assays by both groups confirmed a high-affinity Alk–Jeb interaction. Englund et al. also found that, although the kinase activity of Alk wasn't required for Jeb binding, it was required for Jeb to be taken into the visceral-mesoderm cells and for Jeb's subsequent degradation — point mutations in the catalytic domain prevented Jeb uptake.

Alk therefore seems to be the receptor — or part of a receptor complex — that binds Jeb and subsequently signals through ERK/MAPK to specify visceral-mesoderm founder-cell fate. So Jelly-belly signalling seems to be taking shape.