title: Early downregulation of IGF-I decides the fate of rat retinal ganglion cells after optic nerve injury.
abstract: Retinal ganglion cells (RGCs) die by apoptosis after optic nerve injury. A number of reports have separately shown changes in pro-apoptotic proteins such as the Bcl-2 family members following optic nerve injury. However, induction time of these apoptotic signals has not been identified due to different treatments of the optic nerve, and insufficient time intervals for measurements. Therefore, the stream of cell death signals is not well understood. In the present study, we systematically reinvestigated a detailed time course of these cell death/survival signals in the rat retina after optic nerve crush, to determine the signal cascade leading to RGC apoptosis. The most conspicuous changes detected in the retina were the rapid inactivation of phospho-Akt and phospho-Bad proteins 2-3 days after optic nerve damage, and the subsequent gradual activation of Bax protein and caspase-3 activity accompanied by cell loss of RGCs 6 days after nerve injury. Cellular localization of these molecular changes was limited to RGCs. Furthermore, amount of insulin-like growth factor-I (IGF-I), an activator of the phosphatidyl inositol-3-kinase (PI3K)/Akt system, was initially decreased from RGCs 1-2 days just prior to the inactivation of phospho-Akt by optic nerve crush. Conversely, supplementation with IGF-I into the rat retina induced upregulation of phospho-Akt expression and cell survival of RGCs both in vitro and in vivo. Thus, injury to the optic nerve might induce early changes in cellular homeostasis with a plausible loss of trophic support for injured RGCs. Actually, IGF-I drastically enhanced neurite outgrowth from adult rat RGCs via a wortmannin-dependent mechanism in a retinal explant culture. Our data strongly indicate that IGF-I is a key molecule that induces RGC apoptosis or RGC survival and regeneration in the retina during the early stage of optic nerve injury.
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Homma
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Koriyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mawatari
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Jun
authors.initials: J
authors.lastname: Kosaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015536:Down-Regulation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D009409:Nerve Crush; D020221:Optic Nerve Injuries / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D053148:Caspase 3