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The Journal of Neuroscience, July 4, 2007, 27(27):7222-7233; doi:10.1523/JNEUROSCI.0739-07.2007
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Development/Plasticity/Repair
Glial Scar Expression of CHL1, the Close Homolog of the Adhesion Molecule L1, Limits Recovery after Spinal Cord Injury
Igor Jakovcevski,1 * Junfang Wu,2 * Nicole Karl,1 Iryna Leshchyns'ka,1 Vladimir Sytnyk,1 Jian Chen,2 Andrey Irintchev,1 andMelitta Schachner1,2 1Zentrum für Molekulare Neurobiologie, Universität Hamburg, D-20246 Hamburg, Germany, and 2W. M. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854
Correspondence should be addressed to Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany. Email: melitta.schachner{at}zmnh.uni-hamburg.de
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–/–) mice and wild-type (CHL1+/+) littermates. In contrast to our hypothesis, we found that functional recovery, assessed by locomotor rating and video-based motion analyses, was improved in CHL1–/– 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.
Key words: astrocytes; basic fibroblast growth factor; close homolog of L1; homophilic binding; neurite outgrowth; spinal cord regeneration
Received Feb. 17, 2007; revised May 17, 2007; accepted May 22, 2007.
Correspondence should be addressed to Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany. Email: melitta.schachner{at}zmnh.uni-hamburg.de
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