title: Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion.
abstract: The Hedgehog signalling pathway is crucial for development, adult stem cell maintenance, cell migration and axon guidance in a wide range of organisms. During development, the Hh morphogen directs tissue patterning according to a concentration gradient. Lipid modifications on Hh are needed to achieve graded distribution, leading to debate about how Hh is transported to target cells despite being membrane-tethered. Cytonemes in the region of Hh signalling have been shown to be essential for gradient formation, but the carrier of the morphogen is yet to be defined. Here we show that Hh and its co-receptor Ihog are in exovesicles transported via cytonemes. These exovesicles present protein markers and other features of exosomes. Moreover, the cell machinery for exosome formation is necessary for normal Hh secretion and graded signalling. We propose Hh transport via exosomes along cytonemes as a significant mechanism for the restricted distribution of a lipid-modified morphogen.
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Ana-Citlali
authors.initials: AC
authors.lastname: Gradilla
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.
authors.forename: Esperanza
authors.initials: E
authors.lastname: González
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Seijo
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: German
authors.initials: G
authors.lastname: Andrés
authors.affiliation: University of St Andrews, Biomedical Sciences Research Complex, North Haugh, St Andrews, Scotland KY16 9ST, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bischoff
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: González-Mendez
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Sánchez
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Callejo
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ibáñez
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Milagros
authors.initials: M
authors.lastname: Guerra
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: João Ramalho
authors.initials: JR
authors.lastname: Ortigão-Farias
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.
authors.forename: James D
authors.initials: JD
authors.lastname: Sutherland
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.
authors.forename: Monika
authors.initials: M
authors.lastname: González
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Barrio
authors.affiliation: 1] CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain [2] IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain [3] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Technology Park, 48160 Derio, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Falcón-Pérez
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Guerrero
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D055354:Exosomes / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C510880:iHog protein, Drosophila; C077245:hh protein, Drosophila