Loss of the Heparan Sulfate Proteoglycan Glypican5 Facilitates Long-Range Sonic Hedgehog Signaling

Stem Cells. 2019 Jul;37(7):899-909. doi: 10.1002/stem.3018. Epub 2019 May 13.

Abstract

As a morphogen, Sonic Hedgehog (Shh) mediates signaling at a distance from its sites of synthesis. After secretion, Shh must traverse a distance through the extracellular matrix (ECM) to reach the target cells and activate the Hh response. ECM proteins, in particular, the heparan sulfate proteoglycans (HSPGs) of the glypican family, have both negative and positive effects on Shh signaling, all attributed to their ability to bind Shh. Using mouse embryonic stem cell-derived mosaic tissues with compartments that lack the glycosyltransferases Exostosin1 and Exostosin2, or the HSPG core protein Glypican5, we show that Shh accumulates around its source cells when they are surrounded by cells that have a mutated ECM. This accumulation of Shh is correlated with an increased noncell autonomous Shh response. Our results support a model in which Shh presented on the cell surface accumulates at or near ECM that lacks HSPGs, possibly due to the absence of these Shh sequestering molecules. Stem Cells 2019;37:899-909.

Keywords: Cell signaling; Developmental biology; Embryoid bodies; Embryonic stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Lineage / genetics
  • Cell Movement
  • Embryoid Bodies / cytology
  • Embryoid Bodies / metabolism
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism
  • Gene Editing / methods
  • Gene Expression Regulation, Developmental
  • Genes, Reporter
  • Glypicans / deficiency
  • Glypicans / genetics*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hedgehog Proteins / genetics*
  • Hedgehog Proteins / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • N-Acetylglucosaminyltransferases / deficiency
  • N-Acetylglucosaminyltransferases / genetics*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Protein Transport
  • Red Fluorescent Protein
  • Signal Transduction / genetics*
  • Transfection

Substances

  • Glypicans
  • Hedgehog Proteins
  • Luminescent Proteins
  • Shh protein, mouse
  • Green Fluorescent Proteins
  • N-Acetylglucosaminyltransferases
  • exostosin-1
  • exostosin-2