Presynaptic NCAM Is Required for Motor Neurons to Functionally Expand Their Peripheral Field of Innervation in Partially Denervated Muscles

Chipman, Peter H.; Schachner, Melitta; Rafuse, Victor F.

doi:10.1523/jneurosci.0697-14.2014

Cited by 38 publications

(31 citation statements)

References 71 publications

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“…Interestingly, the proposed model also suggests that activation of NCAM by homophilic and heterophilic interactions at sites of contacts between cells can promote exocytosis of NCAMcontaining vesicles to stabilize these contacts. A recent study shows that presynaptically expressed NCAM is required for the maintenance of the neuromuscular junction innervation field, and it is tempting to speculate that cell surface delivery of NCAM by kinesin-1 is important for stabilizing the neuromuscular junction (Chipman et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In the adult NCAM is involved in regulating synaptic plasticity (Chazal et al, 2000;Chipman et al, 2014;Cremer et al, 1994Cremer et al, , 1997Doherty et al, 1990;Hinsby et al, 2004;Kiryushko et al, 2004;Maness and Schachner, 2007;Muller et al, 1996;Panicker et al, 2003;Sytnyk et al, 2004). Being expressed at the cell surface of neurons and glial cells, NCAM induces intracellular signal transduction pathways and cytoskeleton rearrangements in response to interactions with its extracellular domain (Büttner et al, 2003;Ditlevsen et al, 2008;Leshchyns'ka et al, 2003;Li et al, 2013;Nielsen et al, 2010;Pollerberg et al, 1987;Walmod et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Kinesin-1 promotes post-Golgi trafficking of NCAM140 and NCAM180 to the cell surface

Wobst

Schmitz

Schachner

et al. 2015

Journal of Cell Science

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The neural cell adhesion molecule (NCAM, also known as NCAM1) is important during neural development, because it contributes to neurite outgrowth in response to its ligands at the cell surface. In the adult brain, NCAM is involved in regulating synaptic plasticity. The molecular mechanisms underlying delivery of NCAM to the neuronal cell surface remain poorly understood. We used a protein macroarray and identified the kinesin light chain 1 (KLC1), a component of the kinesin-1 motor protein, as a binding partner of the intracellular domains of the two transmembrane isoforms of NCAM, NCAM140 and NCAM180. KLC1 binds to amino acids CGKAGPGA within the intracellular domain of NCAM and colocalizes with kinesin-1 in the Golgi compartment. Delivery of NCAM180 to the cell surface is increased in CHO cells and neurons co-transfected with kinesin-1. We further demonstrate that the p21-activated kinase 1 (PAK1) competes with KLC1 for binding to the intracellular domain of NCAM and contributes to the regulation of the membrane insertion of NCAM. Our results indicate that NCAM is delivered to the cell surface through a kinesin-1-mediated transport mechanism in a PAK1-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kinesin-1 promotes post-Golgi trafficking of NCAM140 and NCAM180 to the cell surface

Wobst

Schmitz

Schachner

et al. 2015

Journal of Cell Science

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“…NCAM could increase cell surface Lrp4 levels by directly or indirectly binding to Lrp4 and thus stabilizing it on the cell surface. While no evidence that NCAM binds directly to Lrp4 has been reported, it does bind MuSK (Bushell et al, 2008) and possibly other molecules that are clustered at the endplate. It is presently unclear why intracellular Lrp4 levels are greatly reduced in NCAM-deficient myotubes but are not rescued by exogenous expression of NCAM.…”

Section: Discussionmentioning

confidence: 89%

Distinct Roles of Different Presynaptic and Postsynaptic NCAM Isoforms in Early Motoneuron–Myotube Interactions Required for Functional Synapse Formation

Hata

Maeno-Hikichi

Yumoto³

et al. 2017

J. Neurosci.

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The neural cell adhesion molecule (NCAM) is expressed both presynaptically and postsynaptically during neuromuscular junction formation. Genetic deletion in mice of all three isoforms (180, 140, and 120 kDa), or just the 180 isoform, suggested that different isoforms played distinct roles in synaptic maturation. Here we characterized in mice of either sex the earliest adhesive contacts between the growth cones of motoneurons and myotubes and their subsequent maturation into functional synapses in cocultures of motoneurons and myotubes, which expressed their normal complement of NCAM isoforms, or were lacking all isoforms either presynaptically or postsynaptically. Growth cone contact with +/+ mouse myotubes resulted in immediate adhesive contacts and the rapid downregulation of growth cone motility. When contacting NCAM myotubes, growth cones touched and retracted/collapsed multiple times and failed to form stable contacts, even after 10 h. Exogenous expression in myotubes of either the 180 or 140 isoform, but not the 120 kDa isoform, rescued the rapid formation of stable contacts, the accumulation of presynaptic and postsynaptic molecules, and functional transmission. When NCAM was absent only in motoneurons, growth cones did not retract upon myotube contact, but, since their motility was not downregulated, they grew off the ends of the myotubes, failing to form synapses. The agrin receptor Lrp4 was strongly downregulated in NCAM-negative myotubes, and motoneuron growth cones did not make stable contacts with Lrp4-negative myotubes. These studies have identified novel roles for presynaptic and postsynaptic NCAM in mediating early cell-cell interactions required for synapse formation. Although many molecular signals needed to form the functionally effective neuromuscular synapses required for normal movement have been described, the earliest signals that let motoneuron growth cones make stable adhesive contacts with myotubes and cease motility are not well understood. Using dynamic imaging of motoneuron-myotube cocultures, we show that NCAM is required on both the growth cone and myotube and that different NCAM isoforms mediate initial adhesion and the downregulation of growth cone motility. The agrin receptor Lrp4 was also essential for initial adhesive contacts and was downregulated on NCAM myotubes. Our identification of novel roles for NCAM and Lrp4 and possible interactions between them in transforming motile growth cones into stable contacts opens interesting new avenues for exploration.

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“…Thus, the CAPs amplitude relies on the influx and efflux of Na+ and K+ ions, altering the baseline resting potential level (Pandey and Deshpande, 2012). Nerve conduction are used as an indicator to identify nerve activity in signal conduction (Yao et al, 2015) which is important to regulate physical performance, including motor system physiological and pathological processes (Colucci et al, 2009;Chipman et al, 2014). In the peripheral nervous system, decreased neural activity usually indicates a decreased local response or lowered sensitivity to external stimulation.…”

Section: Discussionmentioning

confidence: 99%

Boesenbergia rotunda Ethanolic Extract Inhibits Compound Action Potentials via Opioid Receptors

Gopalsamy

Chia

Ghazali

et al. 2018

LSMB

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Boesenbergia rotunda, traditionally used to relieve stomach, abdomen, joint, muscle, and rheumatic pain was also reported for its antinociceptive effect on a mouse model. However, the possible pain relief effect of Boesenbergia rotunda ethanolic extract (BREE) via the inhibition to the neural pain pathway remains to be elucidated. This study investigated the inhibitory effect of BREE on compound action potentials (CAPs) and the possible involvement of the opioid receptors. The changes in the CAPs amplitudes of the frog's sciatic nerves were evaluated following the exposure to three different dosages of BREE (1, 3 and 10 mg/ml and morphine (3 mg/ml). In another set of experiment, the nerves were pretreated with a non-selective opioid receptor antagonist, naloxone (0.1 mg/ml), before exposing the nerve to BREE (1 mg/ml) to investigate the involvement of opioid receptors in the CAPs inhibitory mechanism. The outcome showed a reduction in the CAPs amplitudes when treated with BREE (1, 3 and 10 mg/ml) whereby the effect was reversible. The CAPs inhibition by BREE was absent when the opioid receptors were blocked. Taken together, these findings suggest that BREE-induced CAPs amplitude reduction involves the activation of opioid receptors.

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Presynaptic NCAM Is Required for Motor Neurons to Functionally Expand Their Peripheral Field of Innervation in Partially Denervated Muscles

Cited by 38 publications

References 71 publications

Kinesin-1 promotes post-Golgi trafficking of NCAM140 and NCAM180 to the cell surface

Kinesin-1 promotes post-Golgi trafficking of NCAM140 and NCAM180 to the cell surface

Distinct Roles of Different Presynaptic and Postsynaptic NCAM Isoforms in Early Motoneuron–Myotube Interactions Required for Functional Synapse Formation

Boesenbergia rotunda Ethanolic Extract Inhibits Compound Action Potentials via Opioid Receptors

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