title: Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms.
abstract: In the vertebrate neural tube, the morphogen Sonic Hedgehog (Shh) establishes a characteristic pattern of gene expression. Here we quantify the Shh gradient in the developing mouse neural tube and show that while the amplitude of the gradient increases over time, the activity of the pathway transcriptional effectors, Gli proteins, initially increases but later decreases. Computational analysis of the pathway suggests three mechanisms that could contribute to this adaptation: transcriptional upregulation of the inhibitory receptor Ptch1, transcriptional downregulation of Gli and the differential stability of active and inactive Gli isoforms. Consistent with this, Gli2 protein expression is downregulated during neural tube patterning and adaptation continues when the pathway is stimulated downstream of Ptch1. Moreover, the Shh-induced upregulation of Gli2 transcription prevents Gli activity levels from adapting in a different cell type, NIH3T3 fibroblasts, despite the upregulation of Ptch1. Multiple mechanisms therefore contribute to the intracellular dynamics of Shh signalling, resulting in different signalling dynamics in different cell types.
authors.affiliation: MRC-National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen
authors.affiliation: MRC-National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Kicheva
authors.affiliation: MRC-National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Ana
authors.identifier: 0000000301329740
authors.initials: A
authors.lastname: Ribeiro
authors.affiliation: MRC-National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Blassberg
authors.affiliation: Department of Mathematics and CoMPLEX, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Page
authors.affiliation: 1] Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK [2] Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Barnes
authors.affiliation: MRC-National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: James
authors.initials: J
authors.lastname: Briscoe
mesh_terms: D000818:Animals; D015536:Down-Regulation; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D054259:Neural Tube / Q000196:embryology* / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D000071676:Zinc Finger Protein GLI1; D049452:Green Fluorescent Proteins
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