Fig. 4. Multiple proteins modulate Shh spread in the neural tube. Schematic of proteins that affect Shh spreading in the ventral neural tube. Several cell surface proteins, including HSPGs, Ptch1, Hhip1, Gas1, Cdo and Boc, interact with extracellular Shh, decreasing its spread (blue arrow) through the neural tube and either enhancing or blocking signaling in a cell-autonomous manner. HSPGs possibly bind extracellular Shh protein and slow its spread through tissue. Ptch1 and Hhip1 both bind and sequester Shh protein, and act as cell-autonomous inhibitors of signal transduction. Gas1, Cdo and Boc also bind and sequester Shh, but act cell-autonomously to promote Shh signaling. Ptch1 and Hhip1 are transcriptional targets of Shh signaling and, consequently, are upregulated in the ventral neural tube as development progresses. By contrast, the positive regulators of signaling, Gas1, Cdo and Boc, are transcriptionally repressed by Shh signaling. Unlike Boc, Gas1 and Cdo are initially expressed in ventral regions of the neural tube, but are subsequently downregulated in response to Shh.