Secreted signaling molecules of the TGF-beta, Wnt, and Hedgehog (Hh) families have been shown to play essential roles in cell fate specification during development. In many developmental contexts, they act as morphogens that emanate from localized sources and form extracellular gradients, which differentially regulate cell fates in a concentration-dependent manner. Our group is studying the function of these morphogens during Drosophila development with higher input in the molecular and cellular mechanisms of Hh signaling. Hh is a molecule highly modified by lipids, which confer to Hh a high affinity for cell membranes. Despite these modifications, Hh protein can signal to cells distant from the source of its production. Presently, we are analyzing how Hh is released and transported through the extracellular matrix. The functional analysis of several proteins with a possible function in this process, such as Ihog, Boi, Dispatched, glypicans, and Shifted/DmWif, suggest that Hh is release through the basolateral side of polarized epithelia, with a previous recycling process from apical tobasolateral (Fig. 1). We are now working on the hipótesis that Hh is then transported in exovesicles attached to cellular extensions called "citonemas" (Fig. 2).
Ihog-RFP and Hh-GFP protein expression in the wing imaginal disc epithelium. Note that Hh-GFP is located in filopodia extensions, also called "cytonemes", and exovesicles in the wing imaginal disc.
Model for processing and release Hh.
A) In the producing cells Hh is translated, cleavage, lipid modified and externalized (red beads). B) Hh is then internalized and sorted to endosomes and to the apical recycling endosomes. In this process Hh probably interacts with Disp (blue discontinue line), Dlp, Dally, Boi (yellow background), and Ihog (green line). Hhis then transported to the basolateral membrane probably within multivesicular endosomes. C) These multivesicular endosomes fuse their membranes with the basolateral plasma membrane to form the cytonemes and release exovesicles. Hh is then transported in exovesicles to its target cells along cytonemes.
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