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Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism

Abstract

Morphogens act in developing tissues to control the spatial arrangement of cellular differentiation1,2. The activity of a morphogen has generally been viewed as a concentration-dependent response to a diffusible signal, but the duration of morphogen signalling can also affect cellular responses3. One such example is the morphogen sonic hedgehog (SHH). In the vertebrate central nervous system and limbs, the pattern of cellular differentiation is controlled by both the amount and the time of SHH exposure4,5,6,7. How these two parameters are interpreted at a cellular level has been unclear. Here we provide evidence that changing the concentration or duration of SHH has an equivalent effect on intracellular signalling. Chick neural cells convert different concentrations of SHH into time-limited periods of signal transduction, such that signal duration is proportional to SHH concentration. This depends on the gradual desensitization of cells to ongoing SHH exposure, mediated by the SHH-dependent upregulation of patched 1 (PTC1), a ligand-binding inhibitor of SHH signalling8. Thus, in addition to its role in shaping the SHH gradient8,9,10, PTC1 participates cell autonomously in gradient sensing. Together, the data reveal a novel strategy for morphogen interpretation, in which the temporal adaptation of cells to a morphogen integrates the concentration and duration of a signal to control differential gene expression.

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Figure 1: The temporal and concentration dependence of the response of neural cells to SHH.
Figure 2: Sustained GLI activity is required for discrimination between OLIG2 and NKX2.2 gene induction.
Figure 3: A cell autonomous function for PTC1-mediated desensitization is required for gradient sensing.

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Acknowledgements

We thank H. Sasaki for the GBS-Luc reporter construct. We are grateful to S. Kales, B. Han and M. Mendelsohn for help in generating Olig2-Cre mice and to A. Gould, J. P. Vincent and V. Ribes for discussions. This work was supported by the MRC (UK). B.G.N. is supported by grants from the Whitehall Foundation, the March of Dimes Foundation, the NINDS and the University of Michigan Biomedical Scholars Program. Olig2-Cre mice were generated with support from HHMI and NINDS to T. M. Jessell. E.D. is supported by EMBO and Marie Curie Fellowships.

Author Contributions E.D. and J.B. conceived the work, performed the experiments, analysed data and wrote the manuscript. L.L.Y and B.G.N. analysed Olig2-Cre mice. K.H., B.C., F.U., A.R. and A.M. provided materials and technical assistance.

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Correspondence to James Briscoe.

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Dessaud, E., Yang, L., Hill, K. et al. Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature 450, 717–720 (2007). https://doi.org/10.1038/nature06347

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