Abstract
Activation of axonal growth program is a critical step in successful optic nerve regeneration following injury. Yet the molecular mechanisms that orchestrate this developmental transition are not fully understood. Here we identified a novel regulator, insulin-like growth factor binding protein-like 1 (IGFBPL1), for the growth of retinal ganglion cell (RGC) axons. Expression of IGFBPL1 correlates with RGC axon growth in development, and acute knockdown of IGFBPL1 with shRNA or IGFBPL1 knockout in vivo impaired RGC axon growth. In contrast, administration of IGFBPL1 promoted axon growth. Moreover, IGFBPL1 bound to insulin-like growth factor 1 (IGF-1) and subsequently induced calcium signaling and mammalian target of rapamycin (mTOR) phosphorylation to stimulate axon elongation. Blockage of IGF-1 signaling abolished IGFBPL1-mediated axon growth, and vice versa, IGF-1 required the presence of IGFBPL1 to promote RGC axon growth. These data reveal a novel element in the control of RGC axon growth and suggest an unknown signaling loop in the regulation of the pleiotropic functions of IGF-1. They suggest new therapeutic target for promoting optic nerve and axon regeneration and repair of the central nervous system.
Highlights
The exuberant growth of axons in the mammalian central nervous system (CNS) becomes markedly reduced as neurons mature
Through analysis of cDNA microarray data obtained from embryonic day 16 (E16) and P0 retinas, a novel secretory protein insulin-like growth factor binding protein-like 1 (IGFBPL1) emerged as a candidate molecule whose levels of expression correlated with retinal ganglion cell (RGC) axon growth capacity
Double-immunolabeling of IGFBPL1 and a primary antibody against β-III-tubulin (Tuj[1]; Fig. 1B and Supplementary Fig. 1) revealed that IGFBPL1 was highly enriched in the ganglion cell layer (GCL) of E16 retinas
Summary
The exuberant growth of axons in the mammalian central nervous system (CNS) becomes markedly reduced as neurons mature. Retinal ganglion cells (RGCs), which have long served as a standard model of CNS neurons, switch off the intrinsic axon growth program during the prenatal period in mice[5,6,7]. One potential mechanism is governed through secretory factors that, when bound to neurons, switch on intracellular axon growth cascades, while their absence turns off the axon growth signals and leads to loss of nerve regenerative capacity. These factors may represent important targets for therapeutic interventions to promote regeneration after CNS injury. IGFBPL1, as a secretory factor that directly regulates axonal growth, may present a possibility for pharmacological manipulation to promote axon regeneration and reverse vision loss after injury in human patients
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