Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury.

Abstract

Extracellular matrix molecule chondroitin sulfate proteoglycans (CSPGs) are highly upregulated in scar tissues and form a potent chemical barrier for CNS axon regeneration. Recent studies support that the receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member leukocyte common antigen related phosphatase (LAR) act as transmembrane receptors to mediate CSPG inhibition. PTPσ deficiency increased regrowth of ascending axons into scar tissues and descending corticospinal tract (CST) axons into the caudal spinal cord after spinal cord injury (SCI). Pharmacological LAR inhibition enhanced serotonergic axon growth in SCI mice. However, transgenic LAR deletion on axon growth in vivo and the role of LAR in regulating regrowth of other fiber tracts have not been studied. Here, we studied the role of LAR in restricting regrowth of injured descending CNS axons in deficient mice. LAR deletion increased regrowth of serotonergic axons into scar tissues and caudal spinal cord after dorsal over-hemitransection. LAR deletion also stimulated regrowth of CST fibers into the caudal spinal cord. LAR protein was upregulated days to weeks after injury and co-localized to serotonergic and CST axons. Moreover, LAR deletion improved functional recovery by increasing BMS locomotor scores and stride length and reducing grid walk errors. This is the first transgenic study that demonstrates the crucial role of LAR in restricting regrowth of injured CNS axons.

• Authors: Bin Xu, Dongsun Park, Yosuke Ohtake, Hui Li, Umar Hayat, Junjun Liu, Michael E Selzer, Frank M Longo, Shuxin Li
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 73 Pg. 36-48 (Jan 2015) ISSN: 1095-953X [Electronic] United States
• PMID: 25220840 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• (3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide
• Benzofurans
• Dextrans
• Quinolines
• biotinylated dextran amine
• Serotonin
• Biotin
• Receptor-Like Protein Tyrosine Phosphatases, Class 2

Topics

• Animals
• Benzofurans
• Biotin (analogs & derivatives)
• Brain (metabolism, pathology)
• Dextrans
• Disease Models, Animal
• Female
• Gene Expression Regulation (physiology)
• Mice
• Mice, Knockout
• Motor Activity (genetics, physiology)
• Mutation (genetics)
• Nerve Regeneration (genetics, physiology)
• Pyramidal Tracts (metabolism, pathology)
• Quinolines
• Receptor-Like Protein Tyrosine Phosphatases, Class 2 (genetics, metabolism)
• Recovery of Function (genetics, physiology)
• Serotonin (metabolism)
• Spinal Cord Injuries (pathology, physiopathology)
• Time Factors