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Figure 1 Neural crest fate restriction models. (a) Direct fate restriction (DFR). In the DFR model, highly multipotent NCC (rainbow colored) generates each fate directly (solid arrow), under direct influence of environmental signals (shown in red). Work in mammals suggests that Wnt signaling is important for both melanocyte and sensory neuron fate specification, with differences in signal timing being key [27]. (b) Progressive fate restriction (PFR). In the PFR model, multipotent NCC rapidly generates a series of intermediate progenitors whose options are restricted. In this schematic, for simplicity, they are shown only as the best-characterized bipotent intermediates (two color), but these models also posit higher potency intermediates as well. The partially restricted (here, bipotent) intermediates then generate individual fates under the influence of environmental signals (red). (c) New cyclical fate restriction (CFR) model. In our novel CFR model, NCCs enter a highly multipotent progenitor state (NC-HMP, grey circle), characterized by a highly dynamic transcriptome, which cycles (dashed arrows) through a series of sub-states; note that this state is highly multipotent (rainbow colors), but each sub-state is biased towards an individual fate (broader band of one color); under the influence of environmental signals (red), cells in each sub-state are driven to adopt an individual fate (solid arrow). Note that these simplified schematics focus on only four key fates?melanocyte (black), Schwann cell (green), sensory neuron (yellow) and sympathetic neuron (cyan)?and on key features of each model