A Hedgehog inhibitor gets around

Cells secrete an inhibitor that controls the distribution and activity of Hedgehog proteins, Holtz et al. show.

The Hedgehog pathway shapes the developing brain, lungs, digestive system, and many other parts of the body. Secreted activators of the pathway can have far-flung effects. However, Hedgehog inhibitors, such as PTCH1 and PTCH2, appear to act locally. They accumulate on the surface of cells that produce them, binding to any Hedgehog proteins that arrive. Researchers thought that the Hedgehog inhibitor HHIP1 was also a homebody.

Holtz et al. found otherwise when they investigated the effects of Hedgehog inhibitors on the developing neural tube of chicken embryos. During spinal cord development, the Hedgehog pathway spurs neural progenitors to divide and stimulates cell fate specification. Inducing progenitor cells to produce versions of PTCH1 or PTCH2 hampered Hedgehog signaling only in those cells. But if the team induced cells to produce HHIP1, the inhibitory effect spread to other cells in the neural tube, suggesting that HHIP1 was secreted. Holtz et al. confirmed that cultured fibroblasts also released the inhibitor.

Secreted HHIP1 was captured by heparan sulfate molecules, which decorate the cell surface and the extracellular matrix. In chicken embryos, HHIP1 accumulated in the basement membrane that surrounds the neural tube and is rich in heparan sulfate. A version of HHIP1 unable to bind heparan sulfate lost much of its ability to block the Hedgehog pathway.

Holtz et al. also detected HHIP1 in the basement membrane of the lungs, where the Hedgehog pathway orchestrates branching of the airways. HHIP1 occurred together with Hedgehog pathway activators in the basement membrane, and its loss altered their distribution. The study indicates that HHIP1’s interaction with heparan sulfate controls its location and thus its influence on the Hedgehog pathway.