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Chenying Guo, Kin-Sang Cho, Kissaou Tchedre, Jie Ma, Christian Antolik, Dong Chen, ; Insulin-like Growth Factor Binding Protein-like 1 (IGFBPL1) as a Potent Regulator of Optic Nerve Regeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1762.
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© ARVO (1962-2015); The Authors (2016-present)
We have recently reported the identification of the insulin-like growth factor binding protein like protein 1 (IGFBPL1) which functions through mediating the bioactivity of IGF-1 to promote the growth of retinal ganglion cell (RGC) axons. To further elucidate the physiological function and signaling events induced by IGFBPL1, we examined igfbpl1 knockout (ibl-/-) mice.
To evaluate the functional significance of IGFBPL1 in vivo, we generated ibl-/- mice and quantified the numbers of RGCs and their axons in wild-type (WT) and ibl-/- mice. Taking advantage of our ability to purify RGCs, we also assessed the survival and axon growth potential of RGCs of WT and ibl-/- mice in culture. The effect of IGFBPL1 in optic nerve regeneration in the adult was investigated further by injecting IGFBPL1 intravitreally into adult mice undergone optic nerve crush injury. Regeneration of the optic nerve was assessed quantitatively by counting RGC axons that were anterogradely labeled with cholera toxin B subunit (CTB). The signaling events underlying IGFBPL1 activity were investigated using RGCs cultures isolated from postnatal day 10 (P10) retinas. Changes of intracellular Ca2+ concentrations and activations of IGF-1 mediated signals, including CREB, Akt, and mTOR were examined, using Ca2+ imaging and Western blot analysis.
ibl-/- mice displayed over 50% reduction in axon numbers in the optic nerves and diminished axonal outgrowth in cultured RGCs purified from the ibl-/- mice, as compared to WT littermate controls. The number of RGCs in ibl-/- mice, however, was only slightly reduced as compared to WT mice. Intravitreal injection of IGFBPL1, in contrast, significantly enhanced optic nerve regeneration post optic nerve injury. Furthermore, we observed that IGFBPL1 promoted calcium signaling and the activation of mTOR in RGCs to promote axonal growth.
IGFBPL1 is a potent regulator of optic nerve growth and regeneration, which functions through IGF-I signaling to promote mTOR phosphorylation and intracellular Ca2+ signaling, the two key downstream effectors that control axonal growth. These results provide novel insights into the molecular events underlying the control of RGC axonal growth and suggest potential new therapeutic strategies for optic nerve protection and regeneration or repair.
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