Article

Franz, C. K., Rutishauser, U. & Rafuse, V. F. Polysialylated neural cell adhesion molecule is necessary for selective targeting of regenerating motor neurons. J. Neurosci. 25, 2081-2091

Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2005; 25(8):2081-91. DOI: 10.1523/JNEUROSCI.4880-04.2005
Source: PubMed

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 (-/-) 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 neurons in wild-type mice preferentially reinnervated muscle pathways, whereas motor neurons in NCAM (-/-) mice reinnervated muscle and 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.

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    • "However, several mechanisms appear to be involved in the beneficial effect that ManNProp has on nerve regeneration. Firstly, the incorporation of N-propionylneuraminic acid (Neu5Prop) and partial replacement of N-acetylneuraminic acid modulates the glycan structure of glycoproteins (such as NCAM) and gangliosides (Buttner et al., 2002;Franz et al., 2005). This is followed by differentiation of the extracellular environment and might be a further interface between regenerating axons and their environment (Brushart et al., 1998). "

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    • "Neuroscience 277 (2014) 356–366 et al., 2007; Zhang et al., 2007a,b; Luo et al., 2011; Jungnickel et al., 2012). Since PSA is prey to rapid degradation by sialidases in a complex tissue environment (Nagai et al., 1989; Martini et al., 1994; Franz et al., 2005), peptide mimics have been screened for and shown to act as bona fide counterparts of PSA (Torregrossa et al., 2004; Mehanna et al., 2009). These linear and cyclic PSA mimetic peptides have shown positive effects in locomotor recovery following peripheral nerve and spinal cord injury in mice (Marino et al., 2009; Mehanna et al., 2009, 2010). "
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    ABSTRACT: In a previous study, we have shown that the small organic compound tegaserod, a drug approved for clinical application in an unrelated condition, is a mimic of the regeneration-beneficial glycan polysialic acid (PSA) in a mouse model of femoral nerve injury. Several independent observations have shown positive effects of PSA and its mimetic peptides in different paradigms of injury of the central and peripheral mammalian nervous systems. Since small organic compounds generally have advantages over metabolically rapidly degraded glycans and the proteolytically vulnerable mimetic peptides, a screen for a small PSA mimetic compound was successfully carried out, and the identified molecule proved to be beneficial in neurite outgrowth in vitro, independent of its originally described function as a 5-HT4 receptor agonist. In the present study, a mouse spinal cord compression device was used to elicit severe compression injury. We show that tegaserod promotes hindlimb motor function at 6 weeks after spinal cord injury compared to the control group receiving vehicle only. Immunohistology of the spinal cord rostral and caudal to the lesion site showed increased numbers of neurons, and a reduced area and intensity of glial fibrillary acidic protein immunoreactivity. Quantification of regrowth/sprouting of axons immunoreactive for tyrosine hydroxylase and serotonin showed increased axonal density rostral and caudal to the injury site in the ventral horns of mice treated with tegaserod. The combined observations suggest that tegaserod has the potential for treatment of spinal cord injuries in higher vertebrates.
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    • "Primary and embryonic stem cell-derived motor neurons from HB9-GFP mice have been used to study neurodegenerative properties of human SOD1 mutations, showing glia and astrocytes with SOD1 mutations induce neurodegeneration of co-cultured SMN even when they do not carry the mutation themselves (Di Giorgio et al., 2007; Nagai et al., 2007). HB9-GFP mice have been used to study motor axon guidance in vivo by Semaphorin signaling (Huber et al., 2005) and in vitro by GDNF chemoattraction and ephrinA signaling (Dudanova et al., 2010) during normal development, targeting of regenerating motor axons in vivo by polysialylated NCAM in the adult (Franz et al., 2005), as well as motor axon development in vivo in mouse models of disease such as SMA (McGovern et al., 2008). Gene Expression Nervous System Atlas (GENSAT) database has been invaluable in providing a detailed library of hundreds of distinct, genetically defined cell populations from engineered mice utilizing BAC (Gong et al., 2003; Gong et al., 2007; Doyle et al., 2008; Schmidt et al., 2013). "
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