Figure 12. Summary diagrams for HH signaling activity and HHIP expression in Control and after HH pathway inhibition, and models for proposed mechanism of action.

(A-C) HH signaling components in fungiform (FP) and filiform (FILIF) papilla. (A) Control: In Typical FP/TB, SHH ligand (green) is present with the TB basal cells. Gli1+ HH-responding cells (blue) are in FP basal epithelial and perigemmal cells. HHIP (red) is within FILIF only. Hedgehog pathway inhibition: (B) In Type II Atypical FP/TB there is reduction of SHH+ cells from TB, loss of Gli1+ cells in one side of the FP wall and associated ectopic HHIP expression at the FP apex on the same side as loss of Gli1+ cells. (C) When Gli1+ cells are completely eliminated from the FP walls along with loss of SHH in Type III Atypical FP/No TB, ectopic HHIP expression occurs in the FP apex in a location previously occupied by the TB. The FP has acquired a conical FILIF-like morphology. (D) In a proposed mechanism of action: In FP, SHH directly and/or indirectly via activating Gli1+ cells inhibits HHIP expression in the papilla. In FILIF, HHIP blocks expression of SHH and downstream Gli1 activity. (E) We propose that the SHH ligand is secreted along FP basal epithelial cells signaling to Gli1+ cells of the FP wall. Concurrently, HHIP from a FILIF cell subset is secreted along basal epithelial cells and inhibits HH signaling. At the rete peg region of the FP/FILIF epithelia, signaling via Gli1+ cells is inhibited.