title: Cubilin, a high affinity receptor for fibroblast growth factor 8, is required for cell survival in the developing vertebrate head.
abstract: Cubilin (Cubn) is a multiligand endocytic receptor critical for the intestinal absorption of vitamin B12 and renal protein reabsorption. During mouse development, Cubn is expressed in both embryonic and extra-embryonic tissues, and Cubn gene inactivation results in early embryo lethality most likely due to the impairment of the function of extra-embryonic Cubn. Here, we focus on the developmental role of Cubn expressed in the embryonic head. We report that Cubn is a novel, interspecies-conserved Fgf receptor. Epiblast-specific inactivation of Cubn in the mouse embryo as well as Cubn silencing in the anterior head of frog or the cephalic neural crest of chick embryos show that Cubn is required during early somite stages to convey survival signals in the developing vertebrate head. Surface plasmon resonance analysis reveals that fibroblast growth factor 8 (Fgf8), a key mediator of cell survival, migration, proliferation, and patterning in the developing head, is a high affinity ligand for Cubn. Cell uptake studies show that binding to Cubn is necessary for the phosphorylation of the Fgf signaling mediators MAPK and Smad1. Although Cubn may not form stable ternary complexes with Fgf receptors (FgfRs), it acts together with and/or is necessary for optimal FgfR activity. We propose that plasma membrane binding of Fgf8, and most likely of the Fgf8 family members Fgf17 and Fgf18, to Cubn improves Fgf ligand endocytosis and availability to FgfRs, thus modulating Fgf signaling activity.
authors.affiliation: Institut de la Vision, INSERM U968, CNRS UMR7210, Université Pierre et Marie Curie UMRS968, 17 Rue Moreau, F-75012 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cases
authors.affiliation: Institut Jacques Monod, CNRS UMR7592, Université Paris Diderot, Sorbonne Paris Cité, 15 Rue Hélène Brion, F-75205 Paris, France.
authors.forename: Aitana
authors.initials: A
authors.lastname: Perea-Gomez
authors.affiliation: Institut de Neurobiologie Alfred-Fessard, CNRS UPR3294, Développement, Evolution et Plasticité du Système Nerveux, F-91198 Gif-sur-Yvette, France.
authors.forename: Diego P
authors.initials: DP
authors.lastname: Aguiar
authors.affiliation: Lundbeck Foundation Research Centre MIND, Department of Biomedicine, University of Aarhus, Olle Worms Allé 3, 8000 Aarhus, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
authors.affiliation: Institut de la Vision, INSERM U968, CNRS UMR7210, Université Pierre et Marie Curie UMRS968, 17 Rue Moreau, F-75012 Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Amsellem
authors.affiliation: Institut de la Vision, INSERM U968, CNRS UMR7210, Université Pierre et Marie Curie UMRS968, 17 Rue Moreau, F-75012 Paris, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Chandellier
authors.affiliation: CNRS UMR7622, Laboratoire de Biologie du Développement, Université Pierre et Marie Curie, 9 Quai Saint Bernard, F-75252 Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Umbhauer
authors.affiliation: CNRS UMR7622, Laboratoire de Biologie du Développement, Université Pierre et Marie Curie, 9 Quai Saint Bernard, F-75252 Paris, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cereghini
authors.affiliation: Department of Biomedicine, University of Aarhus, Olle Worms Allé 3, 8000 Aarhus, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Madsen
authors.affiliation: Institut Jacques Monod, CNRS UMR7592, Université Paris Diderot, Sorbonne Paris Cité, 15 Rue Hélène Brion, F-75205 Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Collignon
authors.affiliation: Institut de la Vision, INSERM U968, CNRS UMR7210, Université Pierre et Marie Curie UMRS968, 17 Rue Moreau, F-75012 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Verroust
authors.affiliation: CNRS UMR7622, Laboratoire de Biologie du Développement, Université Pierre et Marie Curie, 9 Quai Saint Bernard, F-75252 Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Riou
authors.affiliation: Institut de Neurobiologie Alfred-Fessard, CNRS UPR3294, Développement, Evolution et Plasticité du Système Nerveux, F-91198 Gif-sur-Yvette, France.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Creuzet
authors.affiliation: Institut de la Vision, INSERM U968, CNRS UMR7210, Université Pierre et Marie Curie UMRS968, 17 Rue Moreau, F-75012 Paris, France. Electronic address: renata.kozyraki@inserm.fr.
authors.forename: Renata
authors.initials: R
authors.lastname: Kozyraki
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D004705:Endocytosis / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006257:Head / Q000196:embryology*; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000166:cytology / Q000196:embryology*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C484726:Fgf17 protein, mouse; C496457:Fgf8 protein, mouse; D008024:Ligands; D011956:Receptors, Cell Surface; D017468:Receptors, Fibroblast Growth Factor; C029486:intrinsic factor-cobalamin receptor; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Cell Death; Cubilin; Development; Fibroblast Growth Factor (FGF); Megalin; Molecular Cell Biology; Mouse; Xenopus