TAG-1 can mediate homophilic binding, but neurite outgrowth on TAG-1 requires an L1-like molecule and B1 integrins

Howard Hughes Medical Institute, Columbia University, New York, New York 10032.
Neuron (Impact Factor: 15.05). 04/1994; 12(3):675-90. DOI: 10.1016/0896-6273(94)90222-4
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Subsets of axons in the embryonic nervous system transiently express the glycoprotein TAG-1, a member of the subfamily of immunoglobulin (Ig)-like proteins that contain both C2 class Ig and fibronectin type III domains. TAG-1 is attached to the cell surface by a glycosylphosphatidylinositol linkage and is secreted by neurons. In vitro studies have shown that substrate-bound TAG-1 promotes neurite outgrowth. We have examined the nature of axonal receptors that mediate the neurite-outgrowth promoting properties of TAG-1. Although TAG-1 can mediate homophilic binding, neurite outgrowth on a substrate of TAG-1 does not depend on the presence of TAG-1 on the axonal surface. Instead, neurite outgrowth on TAG-1 is inhibited by polyclonal antibodies directed against L1 and, independently, by polyclonal and monoclonal antibodies against beta 1-containing integrins. These results provide evidence that TAG-1 can interact with cell surfaces in both a homophilic and heterophilic manner and suggest that neurite extension on TAG-1 requires the function of both integrins and an L1-like molecule.

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    • "Subsequent differentiation and connectivity of spinal neurons is governed by an assortment of cell type specific transcription factors, defined as a transcriptional code, that controls the expression of receptors for guidance cues [1], [2]. TAG1 and Nfasc are co-expressed in numerous neuronal cell types in the CNS and PNS; both promote neurite outgrowth [24], [38], [39] and both are required for the architecture and function of nodes of Ranvier [40], [41]. In addition, TAG1 is required in vivo for axon guidance [13], [42], [43], neuronal migration [44], [45], and modulates the responses of sensory axons to diffusible guidance signals by controlling the trafficking of their receptors [43]. "
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    ABSTRACT: Cell fate commitment of spinal progenitor neurons is initiated by long-range, midline-derived, morphogens that regulate an array of transcription factors that, in turn, act sequentially or in parallel to control neuronal differentiation. Included among these are transcription factors that regulate the expression of receptors for guidance cues, thereby determining axonal trajectories. The Ig/FNIII superfamily molecules TAG1/Axonin1/CNTN2 (TAG1) and Neurofascin (Nfasc) are co-expressed in numerous neuronal cell types in the CNS and PNS - for example motor, DRG and interneurons - both promote neurite outgrowth and both are required for the architecture and function of nodes of Ranvier. The genes encoding and are adjacent in the genome, an arrangement which is evolutionarily conserved. To study the transcriptional network that governs TAG1 and Nfasc expression in spinal motor and commissural neurons, we set out to identify cis elements that regulate their expression. Two evolutionarily conserved DNA modules, one located between the and genes and the second directly 5' to the first exon and encompassing the first intron of , were identified that direct complementary expression to the CNS and PNS, respectively, of the embryonic hindbrain and spinal cord. Sequential deletions and point mutations of the CNS enhancer element revealed a 130bp element containing three conserved E-boxes required for motor neuron expression. In combination, these two elements appear to recapitulate a major part of the pattern of TAG1 expression in the embryonic nervous system.
    PLoS ONE 02/2013; 8(2):e57960. DOI:10.1371/journal.pone.0057960 · 3.23 Impact Factor
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    • "A possible mechanism is that knock down of contactin-2 expression inhibits the interaction of contactin-2 with the neural cell adhesion molecule L1 (L1.1 in zebrafish), which was shown to be involved in axonal regeneration of lesioned adult zebrafish [14]. It was also shown that the interaction of contactin-2 with L1 promotes neurite outgrowth in vitro [20], [21]. Since contactin-2 acts by homophilic and heterophilic mechanisms that are conducive to neurite outgrowth, secreted contactin-2 may use these mechanisms for recovery under condition of traumatic injury, particularly in view of the possibility that proteases are activated under conditions of trauma. "
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    ABSTRACT: The cell neural adhesion molecule contactin-2 plays a key role in axon extension and guidance, fasciculation, and myelination during development. We thus asked, whether contactin-2 is also important in nervous system regeneration after trauma. In this study, we used an adult zebrafish spinal cord transection model to test the functions of contactin-2 in spinal cord regeneration. The expression patterns of contactin-2 at different time points after spinal cord injury were studied at the mRNA level by qPCR and in situ hybridization, and contactin-2 protein levels and immunohistological localization were detected by Western blot and immunofluorescence analyses, respectively. Contactin-2 mRNA and protein levels were increased along the central canal at 6 days and 11 days after spinal cord injury, suggesting a requirement for contactin-2 in spinal cord regeneration. Co-localization of contactin-2 and islet-1 (a motoneuron marker) was observed in spinal cords before and after injury. To further explore the functions of contactin-2 in regeneration, an anti-sense morpholino was used to knock down the expression of contactin-2 protein by application at the time of injury. Motion analysis showed that inhibition of contactin-2 retarded the recovery of swimming functions when compared to standard control morpholino. Anterograde and retrograde tracing at 6 weeks after injury showed that knock down of contactin-2 inhibited axonal regrowth from NMLF neurons beyond lesion site. The combined observations indicate that contactin-2 contributes to locomotor recovery and successful regrowth of axons after spinal cord injury in adult zebrafish.
    PLoS ONE 12/2012; 7(12):e52376. DOI:10.1371/journal.pone.0052376 · 3.23 Impact Factor
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    • "This complex is required for the clustering of potassium channels at the juxtaparanode in the PNS and in the CNS (Poliak et al. 2003; Savvaki et al. 2008). TAG-1 can also bind heterophically with other cell adhesion molecules such as L1 (Kuhn et al. 1991; Felsenfeld et al. 1994) or NCAM (Milev et al. 1996). Adult TAG-1 null mice show a loss of retinal ganglion cell axons with persistent structural axonal abnormalities linked to myelination defects (Chatzopoulou et al. 2008), as well as shorter internodes in the cerebral and cerebellar white matter (Savvaki et al. 2008). "
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    ABSTRACT: J. Neurochem. (2010) 114, 1243–1260. In multiple sclerosis, CNS demyelination is often followed by spontaneous repair, mostly achieved by adult oligodendrocyte precursor cells. Extent of this myelin repair differs, ranging from very low, limited to the plaque border, to extensive, with remyelination throughout the ‘shadow plaques.’ In addition to restoring neuronal connectivity, new myelin is neuroprotective. It reduces axonal loss and thus disability progression. Reciprocal communication between neurons and oligodendrocytes is essential for both myelin biogenesis and myelin repair. Hence, deciphering neuron-oligodendrocyte communication is not only important for understanding myelination per se, but also the pathophysiology that underlies demyelinating diseases and the development of innovative therapeutic strategies.
    Journal of Neurochemistry 09/2010; 114(5):1243-60. DOI:10.1111/j.1471-4159.2010.06831.x · 4.28 Impact Factor
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