title: Sortilin regulates sorting and secretion of Sonic hedgehog.
abstract: Sonic Hedgehog (Shh) is a secreted morphogen that is an essential regulator of patterning and growth. The Shh full-length protein undergoes autocleavage in the endoplasmic reticulum to generate the biologically active N-terminal fragment (ShhN), which is destined for secretion. We identified sortilin (Sort1), a member of the VPS10P-domain receptor family, as a new Shh trafficking receptor. We demonstrate that Sort-Shh interact by performing coimmunoprecipitation and proximity ligation assays in transfected cells and that they colocalize at the Golgi. Sort1 overexpression causes re-distribution of ShhN and, to a lesser extent, of full-length Shh to the Golgi and reduces Shh secretion. We show loss of Sort1 can partially rescue Hedgehog-associated patterning defects in a mouse model that is deficient in Shh processing, and we show that Sort1 levels negatively regulate anterograde Shh transport in axons in vitro and Hedgehog-dependent axon-glial interactions in vivo Taken together, we conclude that Shh and Sort1 can interact at the level of the Golgi and that Sort1 directs Shh away from the pathways that promote its secretion.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6 Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Charles
authors.initials: C
authors.lastname: Campbell
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6 Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Shawn
authors.initials: S
authors.lastname: Beug
authors.affiliation: Vision Science Division, Krembil Research Institute, University Health Network and Department of Ophthalmology and Vision Sciences, University of Toronto, 60 Leonard Street, Toronto ON M5T 2S8.
authors.forename: Philip E B
authors.initials: PE
authors.lastname: Nickerson
authors.affiliation: Department of Biology, McGill University, 1205 Ave Docteur Penfield Room W4/8, Montreal, Quebec, Canada H3A 1B1 Institut de recherches cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest, Montréal, Quebec, Canada H2W 1R7.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Peng
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mazerolle
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Bassett
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6 Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Randy
authors.initials: R
authors.lastname: Ringuette
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6 Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Fadumo A
authors.initials: FA
authors.lastname: Jama
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, 3640 Rue University, Montréal, Quebec, Canada H3A 0C7.
authors.forename: Carlos
authors.initials: C
authors.lastname: Morales
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors.forename: Annabel
authors.initials: A
authors.lastname: Christ
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6 Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5 Vision Science Division, Krembil Research Institute, University Health Network and Department of Ophthalmology and Vision Sciences, University of Toronto, 60 Leonard Street, Toronto ON M5T 2S8 vwallace@uhnresearch.ca.
authors.forename: Valerie A
authors.identifier: 0000-0003-3721-9017
authors.initials: VA
authors.lastname: Wallace
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001369:Axons / Q000378:metabolism; D016466:CHO Cells; D019556:COS Cells; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D055786:Gene Knockout Techniques; D006056:Golgi Apparatus / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009900:Optic Nerve / Q000378:metabolism; D016716:PC12 Cells; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D012165:Retinal Ganglion Cells / Q000378:metabolism; D055571:Secretory Pathway; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D053823:Hedgehog Proteins; D000099183:Sortilin
keywords: Golgi; Hedgehog; Neuron; Secretion; Sortilin; Trafficking