title: Shh-mediated degradation of Hhip allows cell autonomous and non-cell autonomous Shh signalling.
abstract: The distribution of Sonic Hedgehog (Shh) is a highly regulated and critical process for development. Several negative feedback mechanisms are in place, including the Shh-induced upregulation of Hedgehog-interacting protein (Hhip). Hhip sequesters Shh, leading to a non-cell autonomous inhibition of the pathway. Hhip overexpression has a severe effect on neural tube development, raising the question why normal sites of Hhip expression have a seemingly unimpaired response to Shh. Here we show that although Hhip is able to leave its sites of synthesis to inhibit Shh non-cell autonomously, activation of Smoothened (Smo) drastically increases Hhip internalization and degradation cell autonomously. Although Hhip is unable to cell autonomously inhibit the consequences of Smo activation, it can inhibit the Shh response non-cell autonomously. Our data provide a mechanism by which the Shh ligand can activate the response and negate cell autonomous effects of Hhip, while Hhip can still induce non-cell autonomous inhibition.
authors.affiliation: Department of Molecular and Cell Biology, University of California, 16 Barker Hall, 3204, Berkeley, California 94720, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Kwong
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
authors.forename: Maarten F
authors.initials: MF
authors.lastname: Bijlsma
authors.affiliation: Department of Molecular and Cell Biology, University of California, 16 Barker Hall, 3204, Berkeley, California 94720, USA.
authors.forename: Henk
authors.initials: H
authors.lastname: Roelink
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002642:Chick Embryo; D004285:Dogs; D018274:Electroporation; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D054259:Neural Tube / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D059748:Proteolysis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014162:Transfection; D015053:Zygote
chemical_list: D002352:Carrier Proteins; C117596:HHIP protein, human; D053823:Hedgehog Proteins; D008562:Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor