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First published online July 27, 2006
doi: 10.1242/10.1242/dev.02472

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How does cholesterol affect the way Hedgehog works?

Franz Wendler^*, Xavier Franch-Marro^*, and Jean-Paul Vincent

MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

View larger version (30K): [in a new window]   Fig. 1. Range of Hh activation in the wing disc. (A, part a) A schematic of Drosophila wing imaginal disc staining [adapted from Callejo et al. (Callejo et al, 2006)]. Anterior (A) is to the left. (a,b) Hh-producing cells in the posterior (P) compartment are shown in green. Ptc (red) appears as a stripe that abuts the AP boundary. (A, part c) Expression of relevant target genes. Engrailed (En, blue) and Patched (Ptc, pink) are high threshold targets. Decapentaplegic (Dpp, yellow) and Collier (not shown) are medium threshold targets, and Iroquois (Iro, orange) is a low threshold target. (A, part d) A graphic representation of target activation represented by the colours above, as a function of local Hh concentration. The vertical line represents the AP compartment boundary. (B) Cross-section of a wing imaginal disc. The wing pouch is covered by an epithelium called the peripodial membrane (PM). The lumen between the disc proper cells and the PM is the peripodial space (PS). Here, the PM is highlighted with horse radish peroxidase (HRP) (micrograph courtesy of Laurence Dubois, Centre de Biologie du Développement, Toulouse, France).

View larger version (13K): [in a new window]   Fig. 2. Hh processing and activity in Drosophila wing imaginal discs. (A) A schematic of Hh processing, which involves the removal of the C-terminal half at G257 and the concomitant addition of cholesterol. Palmitic acid is also added onto a N-terminal cysteine, in a reaction catalyzed by Sightless, a membrane bound O-acyltransferase. (B) HhNpalm consists of only the N-terminal part of Hh, which is not cholesterol modified, as the catalytic C-terminal part is missing. The addition of palmitic acid to this form is thought to be unaffected. (C) HhC85Scholes contains a point mutation, replacing cysteine 85 with serine. This form of Hh carries cholesterol but no palmitoyl adduct.

View larger version (44K): [in a new window]   Fig. 3. Two models for Hh transport. A schematic of wing disc epithelia. (A) In model one, Gallet et al. suggest that wild-type Hh is normally secreted and released by Disp on the apical side (Gallet et al., 2006). In the absence of cholesterol, Hh could only be secreted basolaterally, where it would remain confined near the source. If, however, HhNpalm is expressed from peripodial cells (not shown in the diagram), it would flood the peripodial space (at the apical side of the columnar epithelium) and activate low target genes throughout. (B) By contrast, in model two and according to Callejo et al., Hh is also normally secreted and released by Disp on the apical side. However, according to their view, in receiving cells, Hh is normally present in the basolateral space, where it is trapped by either Ptc or HSPGs (Callejo et al., 2006). The binding of Hh to Ptc leads to high threshold target expression and to the sequestration of Hh near its source. Binding of Hh to HSPGs could lead to further transport. Without cholesterol modification, Hh is secreted in a Disp-independent manner on the apical side. There it would be free to spread throughout the disc, but would only activate low-level target genes, possibly via a distinct set of receptors. Because Ptc and HSPGs are not involved in the retention of HhNpalm, no gradient can be formed.