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Yingqian Li, Kin-Sang Cho, Chenying Guo, Tor Paaske Utheim, Dong Feng Chen; IGFBPL1 regulates axon growth through IGF-binding domain. Invest. Ophthalmol. Vis. Sci. 2016;57(12):750.
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Activation of axonal growth program is a critical step in successful nerve regeneration following injury. As a standard model of CNS neurons, retinal ganglion cells (RGCs) shut down the intrinsic axon growth program during the perinatal period in mice. We reported that IGFBPL1 functions as a secretory factor that regulates the intrinsic program for RGC axonal outgrowth. However, the biological activities of the two functional domains of IGFBPL1, immunoglobulin (IG) and IGF-binding (IB) domain remain to be elucidated.
We generated mice deficient in IG domain (KO). RGC and axon counts were carried out in retinal flat-mounts and optic nerve sections, respectively, and compared with that of B6 wild type mice. Axon growth capacities of their RGCs were also assessed in culture. In addition, the functions of IG and IB domains were investigated by overexpressing whole IGFBPL1 protein, IG domain, or IB domain in an RGC cell line.
Absence of IG domain led to increased levels of expression of IB and IGF-1 in IG KO mice. Moreover, we noted increased number of RGC axons in optic nerves of KO mice, when examined at both P0 and adult mice. Correspondingly, the expression of Tuj 1 was increased for ~14-fold, while the expression of GFAP decreased by 2 folds in KO mice as compared to B6 WT mice. Consistently, fluorescence intensity of GFAP in optic nerve sections was largely reduced in KO mice. RGCs isolated from KO mice exhibited increased axon length and improved survival in culture. Overexpression of IG domain resulted in dramatically decreased neurite length while expression of IB domain increased neurite outgrowth.
Our results suggest that the axon growth-promoting effect of IGFBPL1 is mediated primarily by the IB domain, while the IG domain plays an opposing role in RGC axon growth.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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