title: Essential role of heparan sulfates in axon navigation and targeting in the developing visual system.
abstract: Heparan sulfate (HS) is abundant in the developing brain and is a required co-factor for many types of fibroblast growth factor (FGF) signaling in vitro. We report that some HSs, when added exogenously to the developing Xenopus optic pathway, severely disrupt target recognition causing axons from the retina to bypass their primary target, the optic tectum. Significantly, HS sidechains from a neuroepithelial perlecan variant that preferentially bind FGF-2, HS(FGF-2), cause aberrant targeting, whereas those that preferentially bind FGF-1 do not. Charge-matched fragments of HS(FGF-2) show that the mistargeting activity associates with the FGF-binding fragments. Heparitinase removal of native HSs at the beginning of optic tract formation retards retinal axon elongation; addition of FGF-2 restores axon extension but axons lose directionality. Late HS removal, after axons have extended through the tract, elicits a tectal bypass phenotype indicating a growth promoting and guidance function for native HSs. Our results demonstrate that different HS sidechains from the same core protein differentially affect axon growth in vivo, possibly due to their distinct FGF-binding preferences, and suggest that growth factors and HSs are important partners in regulating axon growth and guidance in the developing visual system.
authors.affiliation: Department of Biology 0366, University of California San Diego, La Jolla 92093-0366, USA.
authors.forename: A
authors.initials: A
authors.lastname: Walz
authors.forename: S
authors.initials: S
authors.lastname: McFarlane
authors.forename: Y G
authors.initials: YG
authors.lastname: Brickman
authors.forename: V
authors.initials: V
authors.lastname: Nurcombe
authors.forename: P F
authors.initials: PF
authors.lastname: Bartlett
authors.forename: C E
authors.initials: CE
authors.lastname: Holt
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D001665:Binding Sites; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000502:physiology; D004627:Embryonic Induction / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D006497:Heparan Sulfate / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects; D009900:Optic Nerve / Q000502:physiology; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D012160:Retina / Q000187:drug effects / Q000196:embryology / Q000502:physiology; D014795:Visual Pathways / Q000196:embryology* / Q000502:physiology*; D014982:Xenopus laevis / Q000196:embryology
chemical_list: D016222:Fibroblast Growth Factor 2; D006493:Heparin; D006497:Heparan Sulfate; D011133:Polysaccharide-Lyases; C021349:heparitinsulfate lyase