SECRETION OF THE AMINO-TERMINAL FRAGMENT OF THE HEDGEHOG PROTEIN IS NECESSARY AND SUFFICIENT FOR HEDGEHOG SIGNALING IN DROSOPHILA

Background: The Drosophila segment polarity gene hedgehog encodes a me mber of a family of secreted proteins that are involved in a variety o f patterning processes, in both vertebrates and invertebrates. Some of these processes depend upon short-range or contact-dependent interact ions, whereas others seem to involve long-range signalling. Two differ ent models have been proposed to account for the execution of these co ntrasting processes by the same proteins: one postulates that Hedgehog acts exclusively over short distances, its long-range influences bein g effected through regulation of other signalling factors; the second postulates that different aspects of Hedgehog activity are mediated by distinct forms of the protein that are generated by autoproteolysis. Results: We have investigated these models by mutating the hedgehog co ding region such that only the aminoterminal or carboxy-terminal half of the protein is secreted. Deletion of the carboxy-terminal portion h as little effect on the signalling activity of the protein, whereas ab olishing the secretion of the amino-terminal half leads to a complete loss of signalling. In addition, we find that increases in the level o f expression within the normal hedgehog transcriptional domain of eith er the wild-type protein or the carboxy-terminal-deleted form expand t he range of activity to a limited extent, but have only minor effects on cell identity. Conclusions: In Drosophila, all of the signalling ac tivity of Hedgehog resides in the amino-terminal portion of the protei n, the secretion of which is essential for its function. The range of Hedgehog is limited by the close association of the amino-terminal pep tide with the cell surface but can be extended by elevating the level of its expression.