title: Long-distance axon regeneration in the mature optic nerve: contributions of oncomodulin, cAMP, and pten gene deletion.
abstract: The inability of retinal ganglion cells (RGCs) to regenerate damaged axons through the optic nerve has dire consequences for victims of traumatic nerve injury and certain neurodegenerative diseases. Several strategies have been shown to induce appreciable regeneration in vivo, but the regrowth of axons through the entire optic nerve and on into the brain remains a major challenge. We show here that the induction of a controlled inflammatory response in the eye, when combined with elevation of intracellular cAMP and deletion of the gene encoding pten (phosphatase and tensin homolog), enables RGCs to regenerate axons the full length of the optic nerve in mature mice; approximately half of these axons cross the chiasm, and a rare subset (∼1%) manages to enter the thalamus. Consistent with our previous findings, the axon-promoting effects of inflammation were shown to require the macrophage-derived growth factor Oncomodulin (Ocm). Elevation of cAMP increased the ability of Ocm to bind to its receptors in the inner retina and augmented inflammation-induced regeneration twofold. Inflammation combined with elevated cAMP and PTEN deletion increased activation of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways and augmented regeneration ∼10-fold over the level induced by either pten deletion or Zymosan alone. Thus, treatments that synergistically alter the intrinsic growth state of RGCs produce unprecedented levels of axon regeneration in the optic nerve, a CNS pathway long believed to be incapable of supporting such growth.
authors.affiliation: Laboratory for Neuroscience Research in Neurosurgery and F. M. Kirby Neurobiology Center, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Takuji
authors.initials: T
authors.lastname: Kurimoto
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Yin
authors.forename: Kumiko
authors.initials: K
authors.lastname: Omura
authors.forename: Hui-ya
authors.initials: HY
authors.lastname: Gilbert
authors.forename: Daniel
authors.initials: D
authors.lastname: Kim
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Cen
authors.forename: Lilamarie
authors.initials: L
authors.lastname: Moko
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.forename: Larry I
authors.initials: LI
authors.lastname: Benowitz
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D009900:Optic Nerve / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D002135:Calcium-Binding Proteins; C034733:oncomodulin; D000242:Cyclic AMP; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse