title: No Nogo66- and NgR-mediated inhibition of regenerating axons in the zebrafish optic nerve.
abstract: In contrast to mammals, lesioned axons in the zebrafish (ZF) optic nerve regenerate and restore vision. This correlates with the absence of the NogoA-specific N-terminal domains from the ZF nogo/rtn-4 (reticulon-4) gene that inhibits regeneration in mammals. However, mammalian nogo/rtn-4 carries a second inhibitory C-terminal domain, Nogo-66, being 70% identical with ZF-Nogo66. The present study examines, (1) whether ZF-Nogo66 is inhibitory and effecting similar signaling pathways upon Nogo66-binding to the Nogo66 receptor NgR and its coreceptors, and (2) whether Rat-Nogo66 on fish, and ZF-Nogo66 on mouse neurons, cause inhibition via NgR. Our results from "outgrowth, collapse and contact assays" suggest, surprisingly, that ZF-Nogo66 is growth-permissive for ZF and mouse neurons, quite in contrast to its Rat-Nogo66 homolog which inhibits growth. The opposite effects of ZF- and Rat-Nogo66 are, in both fish and mouse, transmitted by GPI (glycosylphosphatidylinositol)-anchored receptors, including NgR. The high degree of sequence homology in the predicted binding site is consistent with the ability of ZF- and mammalian-Nogo66 to bind to NgRs of both species. Yet, Rat-Nogo66 elicits phosphorylation of the downstream effector cofilin whereas ZF-Nogo66 has no influence on cofilin phosphorylation--probably because of significantly different Rat- versus ZF-Nogo66 sequences outside of the receptor-binding region effecting, by speculation, recruitment of a different set of coreceptors or microdomain association of NgR. Thus, not only was the NogoA-specific domain lost in fish, but Nogo66, the second inhibitory domain in mammals, and its signaling upon binding to NgR, was modified so that ZF-Nogo/RTN-4 does not impair axon regeneration.
authors.affiliation: Developmental Neurobiology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Houari
authors.initials: H
authors.lastname: Abdesselem
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Shypitsyna
authors.forename: Gonzalo P
authors.initials: GP
authors.lastname: Solis
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Bodrikov
authors.forename: Claudia A O
authors.initials: CA
authors.lastname: Stuermer
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000502:physiology*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D020439:Growth Cones / Q000502:physiology; D006367:HeLa Cells; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000502:physiology; D000070798:Nogo Proteins; D009900:Optic Nerve / Q000502:physiology*; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012160:Retina / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000502:physiology; D015398:Signal Transduction; D013045:Species Specificity; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D017261:Glycosylphosphatidylinositols; D009185:Myelin Proteins; D000070798:Nogo Proteins; C541256:Nogo receptor, zebrafish; C000603199:RTN4 protein, human; D011956:Receptors, Cell Surface; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat; C000592544:Rtn4a protein, zebrafish; D029961:Zebrafish Proteins