Promoting Central Regeneration

Abstract

In general, neurons in the mature vertebrate central nervous system fail to regenerate after injury. Intriguingly, however, activation of macrophages in the eye stimulates the regeneration of retinal ganglion cells (RGCs) so that their axons grow down the optic nerve beyond the site of injury (see Filbin). Yin et al. , who previously determined that a fraction of macrophage-secreted proteins less than 20 kD in size promoted axon regeneration, used mass spectrometry of a prominent 10- to 15-kD band and identified oncomodulin, a calcium-binding protein found in tumors. Although inactive on its own, oncomodulin potentiated the ability of mannose plus forskolin to stimulate axon outgrowth in cultured RGCs. Further, absorption of macrophage-conditioned medium (MCM) with anti-oncomodulin IgG eliminated its ability to promote axon growth. Oncomodulin showed specific high-affinity binding to RGCs, which depended on an increase in intracellular adenosine 3′,5′-monophosphate (cAMP, achieved through exposure to forskolin or the cAMP analog 8-bromoadenosine 3′,5′-monophosphate). Pharmacological analysis indicated that oncomodulin activity depended on calcium/calmodulin-dependent protein kinase II (CaMKII) and on gene transcription but not on various mitogen-activated protein kinase kinases or janus kinases. Delivery of oncomodulin- and 8-bromoadenosine 3′,5′-monophosphate-containing microspheres into the vitreous promoted optic nerve regeneration in vivo. Thus, oncomodulin appears to represent a previously unidentified macrophage-derived trophic factor capable of promoting axonal regeneration in at least some central neurons. Y. Yin, M. T. Henzl, B. Lorber, T. Nakazawa, T. T. Thomas, F. Jiang, R. Langer, L. I. Benowitz, Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat. Neurosci. 9 , 843-852 (2006). [PubMed] M. T. Filbin, How inflammation promotes regeneration. Nat. Neurosci. 9 , 715-717 (2006). [PubMed]