Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism.
Morphogens act in developing tissues to control the spatial arrangement of cellular differentiation. 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 responses. 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 exposure. 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 signalling. Thus, in addition to its role in shaping the SHH gradient, 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.
Developmental Neurobiology, National Institute for Medical Research Mill Hill, London NW7 1AA, UK.
Eric
E
Dessaud
Lin Lin
LL
Yang
Katy
K
Hill
Barny
B
Cox
Fausto
F
Ulloa
Ana
A
Ribeiro
Anita
A
Mynett
Bennett G
BG
Novitch
James
J
Briscoe
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002642:Chick Embryo; D005786:Gene Expression Regulation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism* / Q000494:pharmacology; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D054259:Neural Tube / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D015513:Oncogene Proteins / Q000378:metabolism; D051763:PAX7 Transcription Factor / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1
D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D015513:Oncogene Proteins; D051763:PAX7 Transcription Factor; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000071676:Zinc Finger Protein GLI1; C512773:Olig2 protein, mouse; C000606240:Ptch1 protein, mouse