Glial Scar Expression of CHL1, the Close Homolog of the Adhesion Molecule L1, Limits Recovery after Spinal Cord Injury

Abstract

The Ig superfamily adhesion molecule CHL1, the close homolog of the adhesion molecule L1, promotes neurite outgrowth, neuronal migration, and survival in vitro. We tested whether CHL1, similar to its close homolog L1, has a beneficial impact on recovery from spinal cord injury using adult CHL1-deficient (CHL1 Ϫ/Ϫ ) mice and wild-type (CHL1 ϩ/ϩ ) littermates. In contrast to our hypothesis, we found that functional recovery, assessed by locomotor rating and video-based motion analyses, was improved in CHL1 Ϫ/Ϫ mice compared with wild-type mice at 3-6 weeks after compression of the thoracic spinal cord. Better function was associated with enhanced monoaminergic reinnervation of the lumbar spinal cord and altered pattern of posttraumatic synaptic rearrangements around motoneurons. Restricted recovery of wild-type mice was likely related to early and persistent (3-56 d after lesion) upregulation of CHL1 in GFAP-positive astrocytes at the lesion core. In both the intact spinal cord and cultured astrocytes, enhanced expression of CHL1 and GFAP was induced by application of basic fibroblast growth factor, a cytokine involved in the pathophysiology of spinal cord injury. This upregulation was abolished by inhibitors of FGF receptor-dependent extracellular signal-regulated kinase, calcium/calmodulin-dependent kinase, and phosphoinositide-3 kinase signaling pathways. In homogenotypic and heterogenotypic cocultures of neurons and astrocytes, reduced neurite outgrowth was observed only if CHL1 was simultaneously present on both cell types. These findings and novel in vitro evidence for a homophilic CHL1-CHL1 interaction indicate that CHL1 is a glial scar component that restricts posttraumatic axonal growth and remodeling of spinal circuits by homophilic binding mechanisms.

Depletion of Ly6G/Gr-1 Leukocytes after Spinal Cord Injury in Mice Alters Wound Healing and Worsens Neurological Outcome

“…Elevated growth factor levels can sometimes be detrimental; for example, inhibitors to BMPs improve outcome after SCI (Matsuura et al, 2008). Similarly, FGFs increase levels of CHL1, an inhibitor of neurite outgrowth, which may hinder SCI repair (Jakovcevski et al, 2007). Clearly, the implications of altered growth factor responses in neutrophil-depleted mice are complex, and it is likely that the overall expression and spatial location of these factors drive the final outcome toward containment of the injury and endogenous repair.…”

Down-regulation of the axonal polysialic acid–neural cell adhesion molecule expression coincides with the onset of myelination in the human fetal forebrain

“…It is not unusual that cell adhesion molecules show different patterns of expression during development and in regeneration. Another cell adhesion molecule, close homolog of L1, present only on axons during development, is highly expressed by the reactive astrocytes after spinal cord injury (Jakovcevski et al, 2007).…”

Cellular Form of Prion Protein Inhibits Reelin-Mediated Shedding of Caspr from the Neuronal Cell Surface to Potentiate Caspr-Mediated Inhibition of Neurite Outgrowth

“…Areas of the scar required for volume estimation were measured directly under the microscope using Neurolucida software (MicroBrightField). Immunofluorescence labeling of the spinal cord tissue with anti-5-HT and anti-TH antibodies was performed as described previously (Jakovcevski et al, 2007).…”