Abstract
The optic nerve, like most mature CNS pathways, does not regenerate after injury. Through unknown mechanisms, however, macrophage activation in the eye stimulates retinal ganglion cells (RGCs) to regenerate long axons beyond the site of optic nerve injury. Here we identify the calcium (Ca(2+))-binding protein oncomodulin as a potent macrophage-derived growth factor for RGCs and other neurons. Oncomodulin binds to rat RGCs with high affinity in a cyclic AMP (cAMP)-dependent manner and stimulates more extensive outgrowth than other known trophic agents. Depletion of oncomodulin from macrophage-conditioned media (MCM) eliminates the axon-promoting activity of MCM. The effects of oncomodulin involve downstream signaling via Ca(2+)/calmodulin kinase and gene transcription. In vivo, oncomodulin released from microspheres promotes regeneration in the mature rat optic nerve. Oncomodulin also stimulates outgrowth from peripheral sensory neurons. Thus, oncomodulin is a new growth factor for neurons of the mature central and peripheral nervous systems.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Calcium-Binding Proteins / metabolism
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Calcium-Binding Proteins / physiology*
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Calcium-Calmodulin-Dependent Protein Kinase Type 1
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Communication / drug effects
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Cell Communication / physiology
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Cells, Cultured
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Culture Media, Conditioned / pharmacology
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Cyclic AMP / metabolism
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Ganglia, Spinal / cytology
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism
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Growth Cones / drug effects
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Growth Cones / metabolism*
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Growth Cones / ultrastructure
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Growth Substances / metabolism
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Macrophages / metabolism*
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Male
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Nerve Growth Factors / metabolism
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Nerve Regeneration / drug effects
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Nerve Regeneration / physiology*
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Optic Nerve / cytology
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Optic Nerve / drug effects
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Optic Nerve / metabolism
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Rats
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Rats, Inbred F344
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Rats, Sprague-Dawley
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Retinal Ganglion Cells / cytology
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Retinal Ganglion Cells / drug effects
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Retinal Ganglion Cells / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transcriptional Activation / physiology
Substances
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Calcium-Binding Proteins
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Culture Media, Conditioned
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Growth Substances
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Nerve Growth Factors
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oncomodulin
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Cyclic AMP
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Calcium-Calmodulin-Dependent Protein Kinase Type 1
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Calcium-Calmodulin-Dependent Protein Kinases
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Camk1 protein, rat
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Pnck protein, rat
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Calcium