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Chenying Guo, Kin-Sang Cho, Kissaou Tchedre, Jie Ma, Huihui Chen, Taimur Malik, Dong Feng Chen; IGF-1 Binding Protein Like Protein 1 (IGFBPL-1) Promotes Axon Outgrowth In Retinal Ganglion Cells Through The Regulation Of IGF-1 Signaling Pathway. Invest. Ophthalmol. Vis. Sci. 2012;53(14):322.
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IGF-I has been implicated to play an important role in neuronal cell survival and axonal growth, and its effects are mediated through its main receptor IGF-IR. However the underlying mechanisms are not fully understood. We recently found that a newly discovered protein, IGF-I binding protein like protein 1 (IGFBPL-1), regulates the growth of retinal ganglion cell (RGC) axons. Here we propose to elucidate the functional significance and underlying mechanisms of IGFBPL-1 in mediating RGC survival and axon extension in mice.
The expression of IGFBPL-1 in the developing retina was examined in mice at different developmental stages, ranging from embryonic day 16 through adult, using immunohistochemistry, western blot and quantitative RT-PCR. To study the function and underlying signaling event of IGFBPL-1, retinal ganglion cells were purified from mouse pups at postnatal day 0 (P0) and P10, and cultured 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 using LIVE/DEAD® and ß-III-tubulin immunostaining. Knockdowns of IGF-I and IGFBPL-1 signaling were achieved by lentiviral shRNAs or application of inhibitors of IGF-I downstream pathways. Recombinant IGFBPL-1 and/or IGF-I proteins were injected intravitreously into adult C57BL/6 mice on day 0, 3 and 6 post-optic nerve crush to study their effects in vivo. Axonal regeneration following optic nerve crush were quantitatively assessed by labeling RGC axons with an anterograde axon tracer, cholea toxin B subunit (CTB). The number of CTB+ axons extended posterior to the crush site was recorded.
IGFBPL-1 was expressed at a high level in the ganglion cell layer of the retina at E16 but was largely down-regulated postnatally. Addition of IGFBPL-1 alone or together with IGF-I to P0 and P10 RGC cultures significantly promoted axonal extension. Blockade of IGF-I signaling eliminated IGFBPL-1-mediated axonal growth effect. Moreover, intravitreal delivery of IGFBPL-1 significantly promoted optic nerve regeneration following optic nerve injury in adult mice.
IGFBPL-1 is an important regulator of RGC axonal growth during retinal development, likely functioning through the IGF-I signaling pathways. These studies provide new avenues that may fill the knowledge gap of the molecular events regulating RGC axon growth, which will lead to potential therapeutic strategies for optic nerve protection and eventually regeneration or repair.
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