The Inside Scoop on Toll

Science Signaling  02 Nov 2010:
Vol. 3, Issue 146, pp. ec336
DOI: 10.1126/scisignal.3146ec336

In the developing Drosophila embryo, specification of the dorsal-ventral axis depends on signaling through the receptor Toll. Activation of Toll by its ligand Spaetzle leads to movement of the transcription factor Dorsal (the Drosophila homolog of NF-κB) from the cytoplasm into the nucleus. Nuclear concentrations of Dorsal are highest in the ventral portion of the embryo, and its concentration specifies the differentiation of cells later derived from blastoderm nuclei. Lund et al. used live-cell imaging techniques to explore signaling by Toll and found that endocytosed receptor, rather than that at the cell surface, appeared to be critical for its morphogenetic effects. The authors created a fusion protein of green fluorescent protein with Toll to allow its detection in transgenic flies. Unlike antibody staining of the receptor, which showed Toll primarily at the plasma membrane, live imaging showed its localization to be dynamic and that it accumulated in early endosomes along with the marker protein Rab5 within a minute of receptor activation. Blocking endocytosis through expression of an mRNA encoding a dominant-negative version of Rab5 caused local inhibition of Toll signaling and, therefore, of nuclear accumulation of Dorsal. Such local inhibition of Toll internalization on the ventral side of the embryo produced global changes in the Dorsal accumulation in nuclei and essentially inverted the normal dorsal-ventral gradient. The authors discuss how endocytic signaling of Toll may contribute to its function in defining the dorsal-ventral axis. Its internalization along with Spaetzle, its ligand, may help stabilize the gradient of Spaetzle abundance. The nuclei in the Drosophila embryo are in a syncytium at this stage of development, and a stable signaling platform in the endosomes may allow association with individual nuclei so that accumulation of Dorsal can be differentially controlled along the dorsal-ventral axis.

V. K. Lund, Y. DeLotto, R. DeLotto, Endocytosis is required for Toll signaling and shaping of the Dorsal/NF-κB morphogen gradient during Drosophila embryogenesis. Proc. Natl. Acad. Sci. U.S.A. 107, 18028–18033 (2010). [PubMed]