GROWTH FACTOR SIGNALING Restriction by Endocytosis

Key signaling molecules in vertebrate development, such as fibroblast growth factor (FGF), can have short- and long-range regional effects. Their activities are controlled by mechanisms that propagate or restrict their availability to target cells and tissues. Scholpp and Brand have examined how the signaling range of Fgf8 might be controlled in developing zebrafish embryos. By implanting a labeled source of Fgf8 in early embryos, they visualized spreading of the growth factor and determined expression of a target gene encoding sprouty4. Fgf8 was detected in endosomes in cells up to 12 cell diameters away from the source. Host embryos were also injected with various mRNAs to express proteins that interfere with endocytosis. When either a dominant-negative form of the FGF receptor or a Rab5-specific guanosine triphosphatase activating protein (GAP) was expressed to block receptor internalization or inhibit endocytosis, respectively, Fgf8 accumulated outside target cells at greater distances from the source compared with wild-type embryos. If endocytosis was stimulated by expressing more Rab5 protein, the range of Fgf8 spreading and sprouty4 expression was reduced in embryos. The data demonstrate that a Rab5-dependent endocytosis can restrict spreading of diffusible Fgf8, clearing FGF from the extracellular space of target tissues. Because target genes respond to different concentrations of growth factors, endocytosis may serve to shape cellular responses during development.

S. Scholpp, M. Brand, Endocytosis controls spreading and effective signaling range of Fgf8 protein. Curr. Biol. 14, 1834-1841 (2004). [Online Journal]