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The Journal of Neuroscience, May 26, 2004, 24(21):4989-4999; doi:10.1523/JNEUROSCI.4390-03.2004

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Development/Plasticity/Repair
An Oligodendrocyte Lineage-Specific Semaphorin, Sema5A, Inhibits Axon Growth by Retinal Ganglion Cells

Jeffrey L. Goldberg,^1,2 * Mauricio E. Vargas,^1 * Jack T. Wang,¹ Wim Mandemakers,¹ Stephen F. Oster,³ David W. Sretavan,³ and Ben A. Barres¹

¹Stanford University School of Medicine, Department of Neurobiology, Stanford, California 94305, ²Santa Clara Valley Medical Center, San Jose, California 95128, and ³Department of Ophthalmology, University of California, San Francisco, California 94143

In the mammalian CNS, glial cells repel axons during development and inhibit axon regeneration after injury. It is unknown whether the same repulsive axon guidance molecules expressed by glia and their precursors during development also play a role in inhibiting regeneration in the injured CNS. Here we investigate whether optic nerve glial cells express semaphorin family members and, if so, whether these semaphorins inhibit axon growth by retinal ganglion cells (RGCs). We show that each optic nerve glial cell type, astrocytes, oligodendrocytes, and their precursor cells, expressed a distinct complement of semaphorins. One of these, sema5A, was expressed only by purified oligodendrocytes and their precursors, but not by astrocytes, and was present in both normal and axotomized optic nerve but not in peripheral nerves. Sema5A induced collapse of RGC growth cones and inhibited RGC axon growth when presented as a substrate in vitro. To determine whether sema5A might contribute to inhibition of axon growth after injury, we studied the ability of RGCs to extend axons when cultured on postnatal day (P) 4, P8, and adult optic nerve explants and found that axon growth was strongly inhibited. Blocking sema5A using a neutralizing antibody significantly increased RGC axon growth on these optic nerve explants. These data support the hypothesis that sema5A expression by oligodendrocyte lineage cells contributes to the glial cues that inhibit CNS regeneration.

Key words: regeneration; semaphorin; axon guidance; glia; axon growth; optic nerve

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Received Sep 27, 2003; revised April 16, 2004; accepted April 17, 2004.

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