Netrin-1 Is a Chemorepellent for Oligodendrocyte Precursor Cells in the Embryonic Spinal Cord

Abstract

Netrin-1, secreted by floor plate cells, orients axon extension in relation to the ventral midline of the embryonic spinal cord. Oligodendrocyte precursor (OP) cells are born close to the ventral midline and migrate away from the floor plate. Here we show that OP cells, identified by expression of the platelet-derived growth factor alpha receptor, express the netrin receptors dcc and unc5h1 but do not express netrin-1. Using a microchemotaxis assay, we demonstrate that migrating OPs are repelled by a gradient of netrin-1 in vitro. Furthermore, application of netrin-1 to OPs in vitro triggers retraction of OP processes. In the absence of netrin-1 or Deleted in Colorectal Cancer (DCC) function in vivo, fewer OP cells migrate from the ventral to the dorsal embryonic spinal cord, consistent with netrin-1 acting as a repellent. In addition to their role regulating cell movement, DCC and UNC-5 homologs have been suggested to function as proapoptotic dependence receptors, triggering cell death in the absence of netrin-1. In contrast, we report no evidence of increased OP cell death in vivo or in vitro in the absence of either netrin-1 or DCC. These findings indicate that netrin-1 is a repellent cue for migrating OPs in the embryonic spinal cord.

Initiation of Oligodendrocyte Progenitor Cell Migration by a PDGF-A Activated Extracellular Regulated Kinase (ERK) Signaling Pathway

“…The relative band densities of cells treated with PDGF and pharmacological inhibitors shows a clear increase in pERK following PDGF-A treatment, which is not blocked by the addition PD098059, but is markedly reduced in the presence of U0126. pERK levels are also markedly reduced in the presence of AACOCF 3 (Fig. 8c).…”

“…8b, Lane 6). AACOCF 3 showed an apparent reduction in the level of pERK immediately after PDGF-A treatment (Fig. 8b, Lane 7) and at 24 h later (Fig.…”

“…The complex regulatory mechanisms underlying the migration, proliferation and differentiation of OP cells remain to be clearly defined. Several factors are known to play a significant role in OP distribution during brain development, including Netrin-1, which acts to drive OP cells away from the germinal matrix [3]; CXCL1, which acts to stop OP migration and initiate proliferation [4]; extracellular matrix proteins [5] and axonal processes [6].…”

“…However, there is little evidence to support the presence of a PDGF-A chemotactic-gradient in the developing CNS. Recent studies of the role of Netrin-1 as a chemorepellent to drive the OP cells away from the germinal matrix provide compelling evidence that chemorepulsion may direct migration rather than a chemoattractant gradient [3,11]. Therefore, how PDGF signaling impacts OP migration is not yet clear.…”

Netrin-1 signaling mediates NO-induced glial precursor migration and accumulation

“…To test whether the NO-induced cell migration and accumulation could be mediated by axon guidance/migration cues, we first analyzed the expression profile of Netrins in the GPs before and after SNP treatment ( Figure 1Bi-v) because Netrins were reported to be expressed in glial lineage cells [8,9]. The semi-quantitative RT-PCR and immunocytochemistry results indicated that both Netrin-1 and Netrin-4 were up-regulated in the GPs after SNP treatment (Figure 1Bi-v).…”