Netrin-1 Is a Novel Myelin-Associated Inhibitor to Axon Growth

Abstract

We investigated the influence of the bifunctional guidance molecule netrin-1 on axonal growth in the injured adult spinal cord. In the adult, netrin-1 is expressed on mature oligodendrocytes, cells of the central canal, and the meninges. Netrin-1 protein in white matter is selectively enriched adjacent to paranodal loops of myelin in nodes of Ranvier. The repulsion-mediating netrin-1 uncoordinated-5 (UNC5) receptors are expressed by neurons of the corticospinal and rubrospinal projections, and by intrinsic neurons of the spinal cord, both before and after spinal cord injury. Neutralization of netrin-1 in myelin prepared from adult rat spinal cord using UNC5 receptor bodies increases neurite outgrowth from UNC5-expressing spinal motor neurons in vitro. Furthermore, axon regeneration is inhibited in a netrin-1-enriched zone, devoid of other myelin-associated inhibitors, within spinal cord lesion sites in vivo. We conclude that netrin-1 is a novel oligodendrocyte-associated inhibitor that can contribute to axonal growth failure after adult spinal cord injury.

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

“…An inhibitory growth environment for axons has been attributed to products of glial cells, both oligodendrocytes and astrocytes. Myelin-derived inhibitors include Nogo-A (3, 4), myelin-associated glycoprotein (5, 6) (MAG), oligodendrocyteassociated glycoprotein (OMgp), repulsive guidance molecule (RGM) (7), semaphorins (8), and netrins (9). Activated astrocytes at the injury site proliferate to form a glial scar (10,11) and enhance the deposition of inhibitory chondroitin sulfate proteoglycans (12)(13)(14).…”

Spinal Interneuron Axons Spontaneously Regenerate after Spinal Cord Injury in the Adult Feline

“…This suggests that there may be an inherent ability for certain populations of cut axons to respond to guidance cues and cross the midline. Low et al (2008) have shown that cut rubrospinal axons respond to netrin-1 after SCI. However, the study by Low et al (2008) showed that netrin-1 inhibits rubrospinal axon growth rather than guide axons across the midline.…”

A dual promoter lentiviral vector for the in vivo evaluation of gene therapeutic approaches to axon regeneration after spinal cord injury

“…In contrast to corticospinal axons, lesioned rubrospinal axons show a limited degree of spontaneous growth into naive fibroblast grafts placed in the lesion site ( Figure 4g, black arrowheads). 8,19 We then tested a candidate regeneration-enhancing gene, a constitutively active form of 'deleted in colorectal cancer' (DCC), in the above in vivo model of spinal cord injury. DCC is the attraction-mediating receptor for the bimodal ligand netrin-1, which is implicated in directing and accelerating axon outgrowth during CNS development.…”

“…43 The resulting DCC version, myrDCCDP1, can no longer form heteromeric complexes with the repulsion-mediating netrin-1 receptors of the Unc5 family, which are endogenously expressed in adult corticospinal and rubrospinal neurons. 19 Deletion of the P1 domain thus selectively allows myrDCCDP1 homo-complex formation. Overexpression of myrDCCDP1 has previously been shown to enhance axonal growth in vivo when overexpressed in Caenorhabditis elegans neurons.…”

“…[12][13][14][15][16][17][18][19][20] In addition, incomplete recruitment of developmentally expressed sets of growth-associated genes after adult CNS injury is believed to further limit axonal regeneration. Many experimental approaches to enhance CNS plasticity and regeneration therefore focus on identification of novel gene candidates to promote the intrinsic growth capacity of injured adult neurons.…”