title: Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-iduronic acid function as Sonic Hedgehog co-receptors to promote proliferation.
abstract: Sonic Hedgehog (Shh) signaling is crucial for growth, cell fate determination, and axonal guidance in the developing nervous system. Although the receptors Patched (Ptch1) and Smoothened (Smo) are required for Shh signaling, a number of distinct co-receptors contribute to these critical responses to Shh. Several membrane-embedded proteins such as Boc, Cdo, and Gas1 bind Shh and promote signaling. In addition, heparan sulfate proteoglycans (HSPGs) have also been implicated in the initiation of Shh responses. However, the attributes of HSPGs that function as co-receptors for Shh have not yet been defined. Here, we identify HSPGs containing a glypican 5 core protein and 2-O-sulfo-iduronic acid residues at the nonreducing ends of the glycans as co-receptors for Shh. These HSPG co-receptors are expressed by cerebellar granule cell precursors and promote Shh binding and signaling. At the subcellular level, these HSPG co-receptors are located adjacent to the primary cilia that act as Shh signaling organelles. Thus, Shh binds to HSPG co-receptors containing a glypican 5 core and 2-O-sulfo-iduronic acid to promote neural precursor proliferation.
authors.affiliation: From the Dana Farber Cancer Institute, Boston, Massachusetts 02215,; the Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Rochelle M
authors.initials: RM
authors.lastname: Witt
authors.affiliation: the Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1,14476 Potsdam, Germany,; the Federal Institute of Technology (ETH) Zürich, Wolfgang-Pauli-Str.10, CH-8093 Zürich, Switzerland.
authors.forename: Marie-Lyn
authors.initials: ML
authors.lastname: Hecht
authors.affiliation: From the Dana Farber Cancer Institute, Boston, Massachusetts 02215,; the Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Pazyra-Murphy
authors.affiliation: From the Dana Farber Cancer Institute, Boston, Massachusetts 02215,; the Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
authors.affiliation: the Federal Institute of Technology (ETH) Zürich, Wolfgang-Pauli-Str.10, CH-8093 Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Noti
authors.affiliation: the Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen Medical Centre, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: the Lysosomal Diseases Research Unit, SA Pathology at Women's and Children's Hospital, 72 King William Road, North Adelaide, South Australia 5006, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Fuller
authors.affiliation: the Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada, and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.affiliation: the Lysosomal Diseases Research Unit, SA Pathology at Women's and Children's Hospital, 72 King William Road, North Adelaide, South Australia 5006, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
authors.affiliation: the Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1,14476 Potsdam, Germany,; the Institute of Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany. Electronic address: peter.seeberger@mpikg.mpg.de.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeberger
authors.affiliation: From the Dana Farber Cancer Institute, Boston, Massachusetts 02215,; the Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02215,. Electronic address: Rosalind_segal@dfci.harvard.edu.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Segal
mesh_terms: D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000502:physiology; D053673:Glypicans / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C106228:GPC5 protein, human; D053673:Glypicans; C501209:Gpc5 protein, mouse; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; C509239:SHH protein, human; C465570:Shh protein, mouse
keywords: Cerebellum; Hedgehog; Neurodevelopment; Proliferation; Proteoglycan