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Chenying Guo, Kissaou Tchedre, Kin-Sang Cho, Huihui Chen, Taimur Ahmad, Dong Feng Chen; A Novel IGFBP Like Protein (IGFBPL-1) Promotes Axon Outgrowth In Retinal Ganglion Cells Through The Regulation Of IGF-I Signaling Pathway. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4675.
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IGF-I has been shown to play an important role in neuronal cell survival and axon growth, and its effects are mainly mediated through its major receptor IGF-IR. However the underlying mechanisms have not been fully understood. We recently found that a newly discovered protein, IGFBPL-1, may regulate the growth of retinal ganglion cell (RGC) axons. The studies reported here were aimed to elucidate the functional role and mechanisms of IGFBPL-1 on RGC survival and axon extension in mice.
[Expression profile]: The expression pattern of IGFBPL-1 in the developing retina was examined in retinas at different developmental stage, ranging from embryonic day 16 through adult, using immunohistochemistry, western blot and quantitative RT-PCR. [Functional analysis]: Retinal ganglion cells were purified using magnetic beads conjugated with Thy1.2 antibody from new born mouse pups at postnatal day 0 (P0), and cultured for up to five days in the presence or absence of IGFBPL-1 and/or IGF-I proteins. RGC survival and axonal growth were evaluated after three days in culture following LIVE/DEAD® and ß-III-tubulin immunostaining. Lentiviral shRNAs were used to knockdown the expression of IGFBPL-1 and/or IGF-I in culture. [In vivo evaluation]: Functional role of IGFBPL-1 in RGC development was further evaluated in IGFBPL-1 knockout (KO) mouse. RGC morphology and number were recorded using retinal vertical sections or whole-mount preparation. Number of axons in the optic nerve head was counted under electron microscopy. Data collected from the IGFBPL-1 KO mice were compared with that obtained from age-matched wildtype C57BL/6 littermates.
Expression of IGFBPL-1 was restricted to the RGC layer in the retina with a transient high expression at E16-E18 and largely down-regulated postnatally. Addition of IGFBPL-1 alone or together with IGF-I in P0 RGC cultures significantly promoted axonal extension. Mice deficient for IGFBPL-1 exhibit a largely reduced number of axons in the optic nerve without significantly altering the morphology and number of RGCs.
IGFBPL-1 may serve as an important regulator of RGC axonal growth during retinal development, likely functioning by facilitating the IGF-I signaling pathway. These studies provide new information to fill the knowledge gap of understanding the molecular events regulating RGC axon growth, protection, and eventually regeneration or repair.
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