Semaphorin III can repulse and inhibit adult sensory afferents in vivo

Abstract

During development, semaphorins (collapsin, fasciclin) mediate repulsive and inhibitory guidance of neurons. Semaphorin III, a secretable member of this family, is expressed by the ventral spinal cord at the time corresponding to projection of sensory afferents from the dorsal root ganglion (DRG) into the spinal cord. The inhibitory effect of E14 ventral cord is active only on nerve growth factor (NGF)-responsive sensory afferents (small-diameter A-delta and C fibers subserving sensations of temperature and pain). Similarly, COS cells secreting recombinant semaphorin III are able to selectively repel DRG afferents whose growth is stimulated by NGF and not NT-3. However, it is not known whether these molecules can exert a functional role in the fully developed adult peripheral nervous system. In this study, we demonstrated that gene gun transfection and production of semaphorin III in corneal epithelial cells in adult rabbits in vivo can cause repulsion of established A-delta and C fiber trigeminal sensory afferents. In addition, it is shown that, following epithelial wounding and denervation, semaphorin III is able to inhibit collateral nerve sprouts from innervating the reepithelialized tissue. These findings are significant in that they provide direct evidence that small-diameter adult sensory neurons retain the ability to respond to semaphorin III. In addition, the corneal gene gun technique may be generally used to study the in vivo effects of neural growth modulators by quantifying the amount of sensory nerve growth.

MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat

“…The sustained sensitivity of sprouting adult axons to Sema3A in vivo supports the idea that intracellular signaling cues that function downstream of repulsive semaphorins are expressed in adult neurons following injury (Tanelian et al, 1997;Tang et al, 2004). To test this hypothesis, we subjected adult rats to spinal contusion and overhemisection lesions and evaluated MICAL expression in layer V neurons of the motor cortex and in neurons of the red nucleus.…”

“…Fourth, conditioning peripheral nerve injuries that allow DRG axons to regenerate centrally do not promote regenerative axon growth through Sema3-expressing scar tissue (Pasterkamp et al, 2001). The sustained sensitivity of sprouting adult axons to Sema3s in vivo (Tanelian et al, 1997;Tang et al, 2004) supports the idea that intracellular signaling cues mediating repulsive Sema3 signaling are present in injured adult neurons. Consistent with this hypothesis, we observed expression of all three MICAL genes in CST and RST neurons following spinal hemisection and contusion injuries.…”

“…Second, meningeal fibroblast-derived Sema3A inhibits DRG axon growth in vitro, and antibodies capable of blocking neuropilin function promote axon growth in an in vitro model of the CNS scar Shearer et al, 2003). Third, adult CNS and PNS neurons express neuropilins, plexinAs, CRMPs, and MICALs, and sprouting sensory axons are responsive to Sema3-mediated axon repulsion in vitro and in vivo (Agudo et al, 2005;De Winter et al, 2002b;Gavazzi et al, 2000;Lindholm et al, 2004;Owesson et al, 2000;Pasterkamp et al, 1998aPasterkamp et al, ,b, 2000Reza et al, 1999;Tanelian et al, 1997;Tang et al, 2004;Wang and Strittmatter, 1996). Fourth, conditioning peripheral nerve injuries that allow DRG axons to regenerate centrally do not promote regenerative axon growth through Sema3-expressing scar tissue (Pasterkamp et al, 2001).…”

Urodynamic assessment during intravesical infusion of capsaicin for the treatment of refractory detrusor hyperreflexia

“…Semaphorine on the other hand inhibits the development of sensory innervation in vivo and should have an important role in pathological conditions such as paraplegia. 16 …”

Targeting Axon Growth from Neuronal Transplants along Preformed Guidance Pathways in the Adult CNS

“…Peripheral sensory axons also have their growth pathways restricted by the presence of semaphorin 3A in surrounding, nontarget mesenchymal tissue, and both central and peripheral semaphorin expression patterns are spatially and temporally regulated to coincide with the development of sensory nerve tracts (Giger et al, 1996;Masuda and Shiga, 2005). Adult nociceptive sensory fibers are similarly repelled and prevented from sprouting by semaphorin 3A (Tanelian et al, 1997;Tang et al, 2004). Consistent with these findings, the expression of semaphorin 3A dorsal and lateral to the desired ventral turn in the guidance pathway increased the proportion of axons making the "correct" turning decision from 51 to 77%.…”