Sci. STKE, 15 October 2002
Development Dispatching the Hedgehog Signal
The mammalian sonic hedgehog (Shh) protein functions as a secreted ligand that has critical roles in regulation of development. Hedgehog (Hh) proteins are modified by addition of two lipid moieties, a cholesteryl moiety and palmitate, which might be expected to promote association of the Shh protein with membranes of the cells that produce it. However, developmental signaling through Shh requires long-range interactions with receptors on cells that are many cells distant from the cell that produces Shh. In Drosophila, genetic evidence indicates that the protein Dispatched (Disp) takes part in presentation or release of the Hh protein. Ma et al.characterized the mouse homolog of Disp called mDispA. Disruption of the gene encoding mDispA caused developmental defects that reflected a lack of long-range signaling by Shh. Experiments with cultured embryonic fibroblasts lacking mDispA showed that release and extracellular accumulation of Shh were blocked. Exactly how mDispA influences release of Shh remains unclear. However, the Disp proteins are similar in structure to prokaryotic proteins called RND permeases that function as transporters to mediate efflux of molecules from cells. Similarity to RND proteins is also shared by Patched, a protein that functions in responses to Hh at target cells. Thus, the hedgehog pathway appears to have two participants from the RND family that have evolved to serve distinct roles in release and response to Hh ligands.
Y. Ma, A. Erkner, R. Gong, S. Yao, J. Taipale, K. Basler, P. A. Beachy, Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111, 63-75 (2002). [Online Journal]
Citation: Dispatching the Hedgehog Signal. Sci. STKE 2002, tw378 (2002).
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