Cholesterol Modification of Hedgehog Is Required for Trafficking and Movement, Revealing an Asymmetric Cellular Response to Hedgehog

Abstract

Hedgehog family members are secreted proteins involved in numerous patterning mechanisms. Different posttranslational modifications have been shown to modulate Hedgehog biological activity. We investigated the role of these modifications in regulating subcellular localization of Hedgehog in the Drosophila embryonic epithelium. We demonstrate that cholesterol modification of Hedgehog is responsible for its assembly in large punctate structures and apical sorting through the activity of the sterol-sensing domain-containing Dispatched protein. We further show that movement of these specialized structures through the cellular field is contingent upon the activity of proteoglycans synthesized by the heparan sulfate polymerase Tout-Velu. Finally, we show that the Hedgehog large punctate structures are necessary only for a subset of Hedgehog target genes across the parasegmental boundary, suggesting that presentation of Hedgehog from different membrane compartments is responsible for Hedgehog functional diversity in epithelial cells.

A novel PTCH1 mutation in a patient of nevoid basal cell carcinoma syndrome

“…In addition, this mutation is located in sterol-sensing domain associated with trafficking of many proteins including Hedgehog [6], suggesting this domain might play another important role in NBCCS as suggested in a previous report [7].…”

Ventral Neural Progenitors Switch toward an Oligodendroglial Fate in Response to Increased Sonic Hedgehog (Shh) Activity: Involvement of Sulfatase 1 in Modulating Shh Signaling in the Ventral Spinal Cord

“…Our data showing the temporally appropriate expression of ext1 in the ventral neuroepithelium indicate that Sulf1 substrates are synthe-sized locally. Strikingly, the accumulation of Shh at the surface of neural progenitors, either during normal development or after sulf1 overexpression, is visualized as a punctate staining very reminiscent of the large punctate structures (LPSs) described in Drosophila (Gallet et al, 2003;Gallet and Therond, 2005). These structures are involved in the activation of specific target genes in epithelial cells of the epidermis, and ttv, a fly member of ext genes, is required for the transport and/or stability of LPS in the Hedgehog receiving tissue (Bellaiche et al, 1998;The et al, 1999).…”

Making a tooth: growth factors, transcription factors, and stem cells

“…In addition to the reduced molars and fused up incisor, the lower incisor is also missed [73]. In the Hh signaling pathway, Dispatched (Disp) functions within the Hh secreting cells by regulating Hh trafficking within the synthesizing cells, controlling the levels of available Hh signal in the embryo [79,80]. Disp1 has been demonstrated essential for transduction of all Hh signals [81].…”