Polysialylated Neural Cell Adhesion Molecule Is Necessary for Selective Targeting of Regenerating Motor Neurons

Abstract

It is well established that peripheral nerves regenerate after injury. Therefore, incomplete functional recovery usually results from misguided axons rather than a lack of regeneration per se. Despite this knowledge very little is known about the molecular mechanisms regulating axon guidance during regeneration. In the developing neuromuscular system the neural cell adhesion molecule (NCAM) and its polysialic acid (PSA) moiety are essential for proper motor axon guidance. In this study we used a well established model of nerve transection and repair to examine whether NCAM and/or PSA promotes selective regeneration of femoral motor nerves in wild-type and NCAM (Ϫ/Ϫ) mice. We found that regenerating axons innervating the muscle pathway and, to a lesser extent, cutaneous axons in the sensory pathway reexpress high levels of PSA during the time when the cut axons are crossing the lesion site. Second, we found that motor neuronsinwild-typemicepreferentiallyreinnervatedmusclepathways,whereasmotorneuronsinNCAM(Ϫ/Ϫ)micereinnervatedmuscleand cutaneous pathways with equal preference. Preferential regeneration was not observed in wild-type mice when PSA was removed enzymatically from the regenerating nerve, indicating that this form of selective motor axon targeting requires PSA. Finally, transgenic mice were used to show that the number of collateral sprouts, their field of arborization, and the withdrawal of misprojected axons were all attenuated significantly in mice lacking PSA. These results indicate that regenerating motor axons must express polysialylated NCAM, which reduces axon-axon adhesion and enables motor neurons to reinnervate their appropriate muscle targets selectively.

Motoneurons Derived from Embryonic Stem Cells Express Transcription Factors and Develop Phenotypes Characteristic of Medial Motor Column Neurons

“…Although mistargeting of motor axons to the skin was not examined by Tang et al (1992Tang et al ( , 1994, a recent study by Franz et al (2005) showed that regenerating motor axons have a higher than normal propensity to grow along cutaneous nerves if they do not express PSA. Inspired by these studies, we investigated whether PSA was differentially expressed by eGFP ϩ axons innervating the longissimus muscle and skin.…”

Polysialyltransferase expression is linked to neuronal migration in the developing and adult zebrafish

“…Therefore, recombinant EndoN enzyme, which selectively degrades polySia residues from NCAM (Rutishauser et al, 1985;Marx et al, 2001;Franz et al, 2005), was used to specifically remove PSA from the differentiating brain at 33 hpf, shortly after the onset of PSA-NCAM expression in the cerebellum (Marx et al, 2001). The efficiency of PSA removal in EndoN-and phosphate buffered saline (PBS) -treated control embryos was monitored by immunohistochemistry using the mAb735 anti-PSA antibody at 2 and 24 hr after injection.…”

Physiological Exploration of the Long Term Evolutionary Selection against Expression of N-Glycolylneuraminic Acid in the Brain

“…Another characteristic of sialylated glycan structure in the brain is polysialic acid (polySia), 3 a homopolymer of Ͼ90 sialic acid residues attached to selected proteins (13,14). PolySia modulates cell-cell interactions, thus playing important roles in neuronal development and regeneration (15)(16)(17). Recently, it was suggested that polySia also serves as a reservoir of growth factors (18,19).…”