Dr. Ute Pickhinke


University of Münster
Institute for Physiological Chemistry & Pathobiochemistry
48143 Münster
Germany
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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 (Ohlig et al, 2012). I found that purified glycosaminoglycan mixtures release N- and C-terminally truncated Shh morphogens from the surface of producing cells. Consistent with this, I found that the same GAG isolates drive the conversion of soluble, tagged morphogens into truncated forms with strongly increased bioactivity (Pickhinke, in revision). On the cell surface, increasing the relative level of Shh N-palmitoylation via IRES-mediated coexpression of Hedgehog acyltransferase (Hhat) increases Shh processing and bioactivity (Pickhinke, submitted). Lastly, I found that IRES-mediated coexpression of wild-type and HS-deficient, mutant Glypican family members 1-6 strongly affects palmitoylation-dependent processing as well as Shh release and bioactivity (unpublished). This suggests HSPG functions in Shh release and activation (Ohlig et al, 2011).

Last update 06.05.2013


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