Synergy and convergence of pathways controlling functional regeneration in the spinal cord

Abstract

Barriers to regeneration in the mammalian central nervous system (CNS) include the presence of inhibitory factors like myelin-associated glycoprotein (MAG) that block re-growth of injured axons. Inhibition by MAG antagonizes the induction of integrin-based substrate adhesions in axonal growth cones by brain-derived neurotrophic factor (BDNF). Here, using a novel approach to overcome inhibitory actions of MAG by activating integrins, we provide cellular and molecular evidence that integrin activity modulates the actions of chemotropic cues on substrate adhesions and supports axon regeneration in vertebrates. Potentiating integrin activity in cultured spinal neurons blocked negative integrin remodeling and inhibition of axon outgrowth induced by MAG, but also restored BDNF-dependent integrin clustering and stimulated outgrowth. In a zebrafish complete spinal cord transection model, combined integrin activation and BDNF treatment synergistically triggered functional regeneration of long projection axons that lack regenerative capacity from the hindbrain. The combined treatment also promoted functional repair even in the presence of exogenous mammalian inhibitory factors, including MAG, which alone impaired recovery of swimming movements. Thus, integrin activation state plays complementary roles in modulating the output activity of opposing cues on integrin-based adhesions and supports functional nerve regeneration in vivo. Our findings reveal effective reversal of downstream actions of inhibitory cues, thereby overcoming a major barrier to regeneration in the mammalian CNS, while simultaneously supporting neurotrophin-stimulated outgrowth. Discovery of therapeutic strategies targeting integrin activation state therefore holds promise for promoting axon regeneration after traumatic injury, which is a critical step in restoring connectivity and functional recovery.