title: Ptch2 mediates the Shh response in Ptch1-/- cells.
abstract: The Hedgehog (Hh) signaling response is regulated by the interaction of three key components that include the sonic hedgehog (Shh) ligand, its receptor patched 1 (Ptch1) and the pathway activator smoothened (Smo). Under the prevailing model of Shh pathway activation, the binding of Shh to Ptch1 (the key Shh receptor) results in the release of Ptch1-mediated inhibition of Smo, leading to Smo activation and subsequent cell-autonomous activation of the Shh response. Consistent with this model, Ptch1(-/-) cells show a strong upregulation of the Shh response. Our finding that this response can be inhibited by the Shh-blocking antibody 5E1 indicates that the Shh response in Ptch1(-/-) cells remains ligand dependent. Furthermore, we find that Shh induces a strong response in Ptch1(-/-);Shh(-/-) cells, and that Ptch1(-/-) fibroblasts retain their ability to migrate towards Shh, demonstrating that Ptch1(-/-) cells remain sensitive to Shh. Expression of a dominant-negative Ptch1 mutant in the developing chick neural tube had no effect on Shh-mediated patterning, but expression of a dominant-negative form of patched 2 (Ptch2) caused an activation of the Shh response. This indicates that, at early developmental stages, Ptch2 functions to suppress Shh signaling. We found that Ptch1(-/-);Ptch2(-/-) cells cannot further activate the Shh response, demonstrating that Ptch2 mediates the response to Shh in the absence of Ptch1.
authors.affiliation: Department of Molecular and Cell Biology, 16 Barker Hall, 3204, University of California, Berkeley, CA 94720, USA.
authors.forename: Astrid C
authors.initials: AC
authors.lastname: Alfaro
authors.affiliation: Department of Molecular and Cell Biology, 16 Barker Hall, 3204, University of California, Berkeley, CA 94720, USA.
authors.forename: Brock
authors.initials: B
authors.lastname: Roberts
authors.affiliation: Department of Molecular and Cell Biology, 16 Barker Hall, 3204, University of California, Berkeley, CA 94720, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Kwong
authors.affiliation: Department of Molecular and Cell Biology, 16 Barker Hall, 3204, University of California, Berkeley, CA 94720, USA.
authors.forename: Maarten F
authors.initials: MF
authors.lastname: Bijlsma
authors.affiliation: Department of Molecular and Cell Biology, 16 Barker Hall, 3204, University of California, Berkeley, CA 94720, USA roelink@berkeley.edu.
authors.forename: Henk
authors.initials: H
authors.lastname: Roelink
mesh_terms: D000818:Animals; D017920:Antiporters / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002633:Chemotaxis; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000072082:Patched-2 Receptor; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011522:Protons; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor
chemical_list: D017920:Antiporters; C510745:Boc protein, mouse; C510744:Cdon protein, mouse; D015815:Cell Adhesion Molecules; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; C000606236:PTCH1 protein, human; C000606238:PTCH2 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000072082:Patched-2 Receptor; D011522:Protons; C000606240:Ptch1 protein, mouse; C000606241:Ptch2 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor
keywords: Genome editing; Mouse embryonic stem cells; Patched1; Patched2; Shh
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