The Long-Range Activity of Hedgehog Is Regulated in the Apical Extracellular Space by the Glypican Dally and the Hydrolase Notum

SummaryCell fate determination during developmental patterning is often controlled by concentration gradients of morphogens. In the epithelial field, morphogens like the Hedgehog (Hh) peptides diffuse both apically and basolaterally; however, whether both pools of Hh are sensed at the cellular level is unclear. Here, we show that interfering with the amount of apical Hh causes a dramatic change in the long-range activation of low-threshold Hh target genes, without similar effect on short-range, high-threshold targets. We provide genetic evidence that the glypican Dally upregulates apical Hh levels, and that the release of Dally by the hydrolase Notum promotes apical Hh long-range activity. Our data suggest that several pools of Hh are perceived in epithelial tissues. Thus, we propose that the overall gradient of Hh is a composite of pools secreted by different routes (apical and basolateral), and that a cellular summation of these components is required for appropriate developmental patterning.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (351 K)Download as PowerPoint slideHighlights► Apical Hh is responsible for long-range activation of low-threshold target genes ► The glypican Dally upregulates apical Hh levels ► Release of Dally by the PLC-like Notum promotes apical Hh long-range activity