Fig. 6. A `temporal adaptation' model for interpreting graded Shh signaling. (A) A model for the spatial and temporal specification of progenitor cells during exposure to Shh secreted from a ventral source. At early time points (t₀), Ptch1 expression levels (brown receptor) in neural progenitors are low, consequently low levels of Shh protein (blue) are sufficient to bind the available Ptch1. This produces high levels of Smo signal transduction (green) and, consequently, high levels of positive Gli activity (GliA, red), even in cells that are exposed to a low concentration of Shh (cell 3, t₀). The upregulation of Ptch1 (and possibly other negative regulators of the pathway) by Shh signaling (t₁) increases the level of Ptch1 in responding cells. As a result, the concentration of Shh necessary to sustain high levels of signal transduction increases with time (t₁). In cells exposed to concentrations of Shh insufficient to bind all of the raised level of Ptch1 (cell 3, t₁), the level of GliA declines (GliA, orange). This process of cell-autonomous desensitization continues (t₂), resulting in distinct temporal profiles of Gli activity in cells arrayed along the DV axis. In addition, the upregulation of ligand-binding inhibitors of Shh signaling, including Ptch1, results in the sequestration of Shh protein in more-ventral regions of the neural tube (cell 1). Both the level and the duration of Shh-Gli activity influence the gene expression profile in responding cells. Low levels of Gli activity, for example produced by the partial inhibition of the generation of GliR activity, are sufficient to repress Pax7 (cell 4, t₁). The duration of Shh signaling is partially responsible for the distinction between Olig2 and Nkx2.2 induction. High levels of Gli activity induce Olig2 expression (cells 1-2, t₁). If the levels of signaling are sustained (cell 1, t₂), Nkx2.2 is induced and Olig2 is repressed. By contrast, if the levels of signaling in a cell decline prior to this time point, Olig2 expression is consolidated (cell 2, t₂). (B) The response of the indicated cells in A to Shh can be represented as a function of both Gli activity and the duration of Shh exposure (time). The adaptation of cells to ongoing Shh signaling results in different concentrations of Shh producing distinct profiles of Gli activity. Hence, temporal adaptation transforms different concentrations of morphogen into corresponding durations of increased Gli activity. In this view, the induction of each progenitor state requires exposure to a concentration of Shh above a defined threshold for a distinct period of time.