Article

Axon-Glia Interactions and the Domain Organization of Myelinated Axons Requires Neurexin IV/Caspr/Paranodin

Cardiovascular Research Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Neuron (Impact Factor: 15.05). 06/2001; 30(2):369-83. DOI: 10.1016/S0896-6273(01)00294-X
Source: PubMed

ABSTRACT

Myelinated fibers are organized into distinct domains that are necessary for saltatory conduction. These domains include the nodes of Ranvier and the flanking paranodal regions where glial cells closely appose and form specialized septate-like junctions with axons. These junctions contain a Drosophila Neurexin IV-related protein, Caspr/Paranodin (NCP1). Mice that lack NCP1 exhibit tremor, ataxia, and significant motor paresis. In the absence of NCP1, normal paranodal junctions fail to form, and the organization of the paranodal loops is disrupted. Contactin is undetectable in the paranodes, and K(+) channels are displaced from the juxtaparanodal into the paranodal domains. Loss of NCP1 also results in a severe decrease in peripheral nerve conduction velocity. These results show a critical role for NCP1 in the delineation of specific axonal domains and the axon-glia interactions required for normal saltatory conduction.

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    • "Caspr4-deficient mice show decreased neurotransmission in the GABAergic system and an elevated release of dopamine, resulting in abnormal sensory-motor gating and grooming endophenotypes (Karayannis et al. 2014). Similar to Caspr2, Caspr has been well studied in the formation and maintenance of polarized domains of myelinated axons (Peles and Salzer 2000; Bhat et al. 2001; Buttermore et al. 2013; Gordon et al. 2014), but other functions of Caspr in the brain have not been investigated. However, some binding partners of Caspr have been identified, thereby allowing inferences about its functions in interactions with native prion protein and F3/contactin, which are involved in neurite outgrowth (Buttiglione et al. 1998; Chen et al. 2003; Santuccione et al. 2005; Zacharias and Rauch 2006; Pantera et al. 2009; Devanathan et al. 2010; Loubet et al. 2012), neural proliferation, cortical neurogenesis (Bizzoca et al. 2003, 2012; Steele et al. 2006; Santos et al. 2011; Xenaki et al. 2011; Puzzo et al. 2013; Prodromidou et al. 2014), and synaptic plasticity (Caiati et al. 2013; Puzzo et al. 2015). "
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    ABSTRACT: The generation of layer-specific neurons and astrocytes by radial glial cells during development of the cerebral cortex follows a precise temporal sequence, which is regulated by intrinsic and extrinsic factors. The molecular mechanisms controlling the timely generation of layer-specific neurons and astrocytes remain not fully understood. In this study, we show that the adhesion molecule contactin-associated protein (Caspr), which is involved in the maintenance of the polarized domains of myelinated axons, is essential for the timing of generation of neurons and astrocytes in the developing mouse cerebral cortex. Caspr is expressed by radial glial cells, which are neural progenitor cells that generate both neurons and astrocytes. Absence of Caspr in neural progenitor cells delays the production cortical neurons and induces precocious formation of cortical astrocytes, without affecting the numbers of progenitor cells. At the molecular level, Caspr cooperates with the intracellular domain of Notch to repress transcription of the Notch effector Hes1. Suppression of Notch signaling via a Hes1 shRNA rescues the abnormal neurogenesis and astrogenesis in Caspr-deficient mice. These findings establish Caspr as a novel key regulator that controls the temporal specification of cell fate in radial glial cells of the developing cerebral cortex through Notch signaling.
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    • "The contactin-1–Caspr interaction is required for the transport and intracellular processing of contactin-1 (Gollan et al. 2003). Blocking the interaction between NF155 and the Caspr/contactin-1 complex inhibits myelination (Charles et al. 2002) and genetic ablation of genes encoding Caspr, contactin-1 or NF155 results both in the disruption of the paranodal septate-like junctions and in loss of ion channel segregation and impaired nerve conduction (Boyle et al. 2001; Bhat et al. 2001; Thaxton et al. 2010). In conclusion, interaction of glial NF155 with the axonal Caspr/contactin-1 complex is required for both nodal and paranodal stability. "
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    • "The biggest structural difference is that in the PNS, the nodes of Ranvier are apposed by nodal microvilli emanating from myelinating Schwann cells. These microvilli may play a role in local ion buffering, but also express gliomedin, a glial protein known to be important for the clustering of Nav channels at PNS nodes of Ranvier (for more information on PNS nodes of Ranvier see [13, 122]). Although CNS nodes of Ranvier are not contacted by protrusions of oligodendrocytes, they are often closely associated with astrocytic processes, the function of which remains unknown [58, 59]. "
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    ABSTRACT: Healthy nodes of Ranvier are crucial for action potential propagation along myelinated axons, both in the central and in the peripheral nervous system. Surprisingly, the node of Ranvier has often been neglected when describing CNS disorders, with most pathologies classified simply as being due to neuronal defects in the grey matter or due to oligodendrocyte damage in the white matter. However, recent studies have highlighted changes that occur in pathological conditions at the node of Ranvier, and at the associated paranodal and juxtaparanodal regions where neurons and myelinating glial cells interact. Lengthening of the node of Ranvier, failure of the electrically resistive seal between the myelin and the axon at the paranode, and retraction of myelin to expose voltage-gated K(+) channels in the juxtaparanode, may contribute to altering the function of myelinated axons in a wide range of diseases, including stroke, spinal cord injury and multiple sclerosis. Here, we review the principles by which the node of Ranvier operates and its molecular structure, and thus explain how defects at the node and paranode contribute to neurological disorders.
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