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.
"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). "
[Show abstract][Hide abstract] 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.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Corticospinal motor neurons (CSMN) have a unique ability to receive, integrate, translate, and transmit the cerebral cortex's input toward spinal cord targets and therefore act as a "spokesperson" for the initiation and modulation of voluntary movements that require cortical input. CSMN degeneration has an immense impact on motor neuron circuitry and is one of the underlying causes of numerous neurodegenerative diseases, such as primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS). In addition, CSMN death results in long-term paralysis in spinal cord injury patients. Detailed cellular analyses are crucial to gain a better understanding of the pathologies underlying CSMN degeneration. However, visualizing and identifying these vulnerable neuron populations in the complex and heterogeneous environment of the cerebral cortex have proved challenging. Here, we will review recent developments and current applications of novel strategies that reveal the cellular and molecular basis of CSMN health and vulnerability. Such studies hold promise for building long-term effective treatment solutions in the near future.
Frontiers in Neuroanatomy 03/2014; 8:16. DOI:10.3389/fnana.2014.00016 · 3.54 Impact Factor
"Since PSA is rapidly degraded by sialidases in the complex tissue environment (Franz et al., 2005; Martini et al., 1994; Nagai et al., 1989) peptide mimetics of PSA were identified and shown to act as true functional counterparts of PSA (Torregrossa et al., 2004). Linear and cyclic PSA mimetic peptides have improved functional recovery following peripheral nerve and spinal cord injuries in mice (Marino et al., 2009; Mehanna et al., 2010; Mehanna et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Glycans attached to the cell surface via proteins or lipids or exposed in the extracellular matrix affect many cellular processes, including neuritogenesis, cell survival and migration, as well as synaptic activity and plasticity. These functions make glycans attractive molecules for stimulating repair of the injured nervous system. Yet, glycans are often difficult to synthesize or isolate and have the disadvantage to be unstable in a complex tissue environment. To circumvent these issues, we have screened a library of small organic compounds to search for structural and functional mimetics of the neurostimulatory glycan polysialic acid (PSA) and identified the 5-HT4 receptor agonist tegaserod as a PSA mimetic. The PSA mimicking activity of tegaserod was shown in cultures of central and peripheral nervous system cells of the mouse and found to be independent of its described function as a serotonin (5-HT4) receptor agonist. In an in vivo model for peripheral nerve regeneration, mice receiving tegaserod at the site of injury showed enhanced recovery compared to control mice receiving vehicle control as evidenced by functional measurements and histology. These data indicate that tegaserod could be be repurposed for treatment of nervous system injuries and underscores the potential of using small molecules as mimetics of neurostimulatory glycans.
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