Axon regeneration in the mature optic nerve

The optic nerve conveys visual information from the eye to the brain. Axons that are injured in the optic nerve normally can not regenerate, and their parent cell bodies, the retinal ganglion cells, soon begin to die. Several years ago, we discovered that stimulating an inflammatory reaction in the eye causes retinal ganglion cells (RGCs) to revert to an active growth state and to regenerate their axons through the optic nerve. Using a cell culture model developed in this lab, we discovered that this regeneration requires the combination of a low molecular weight factor that is constitutively present in the eye, elevation of intracellular cAMP, and a protein that is secreted by macrophages. Through biochemical purification methods and mass spectrometry, we identified the low molecular weight growth factor as the carbohydrate mannose. The macrophage-derived protein has now been identified by Dr. Yuqin Yin in our group as a small Ca2+-binding protein oncomodulin. Dr. Yin showed that oncomodulin is actively secreted from macrophages, binds to a cell-surface receptor on RGCs with high affinity and specificity, and, in the presence of appropriate co-factors, stimulates more extensive outgrowth than other well-known trophic factors. Most significantly, the release of oncomodulin from polymeric beads stimulates extensive re-generation in the mature mammalian optic nerve.

Additional work from this lab has shown that when we combine methods to reactivate neurons’ intrinsic growth state with methods to overcome the inhibitory signals that normally inhibit growth in the mature CNS, we can get even more extensive regeneration. Ongoing work is now aimed at identifying the receptor for oncomodulin, the molecular machinery that leads to axon growth, and its effects on other cells in the nervous system and in other systems.