The biological function of all vertebrate and invertebrate Hedgehog (Hh) morphogen family members depends on the regulated expression of Heparan sulfate (HS) proteoglycans. Targeted deletion of HS biosynthetic enzymes, as well as targeted deletion of glypican core proteins results in developmental defects strongly resembling those found in mouse or fly embryos deficient in Hh function. Based on our initial observation of Sonic hedgehog (Shh, ShhNp represents the active soluble morphogen) related phenotypes in mice made deficient in HS biosynthesis in our lab, I aimed to understand the basis of this essential interaction in molecular detail. To this end, I characterized Shh release and activation in vitro and in vivo. I found that ADAMs (a Disintegrin and Metalloproteases) release N- and C-terminally truncated morphogens from the surface of producing cells. Moreover, I found that Shh N-palmitoylation (via membrane-proximal positioning of the cleavage site) is the prerequisite for proteolytic cleavage of an N-terminal peptide during solubilization, and that removal of this palmitoylated peptide is essential for ShhNp bioactivation during release (Ohlig et al., 2011). Lastly, I found that the N-terminal, HS-binding Cardin-Weintraub motif serves as the sheddase cleavage site (Ohlig et al, 2012). Thus, HS-binding of solubilized Shh is strongly impaired, allowing it to diffuse through the HS-rich extracellular matrix.

REFERENCES

• Ohlig S, Farshi P, Pickhinke U, van den Boom J, Höing S, Jakuschev S, Hoffmann D, Dreier R, Schöler HR, Dierker T, Bordych C and Grobe K(2011) Sonic Hedgehog Shedding Results in Functional Activation of the Solubilized Protein. Dev. Cell 20: 764-774
• Ohlig S, Pickhinke U, Sirko S, Bandari S, Hoffmann D, Dreier R, Farshi P, Götz M and Grobe K (2012) An emerging role of Sonic hedgehog shedding as a modulator of heparan sulfate interactions. J. Biol Chem 287: 43708-19

Last update 06.05.2013

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