Neural Cell Adhesion Molecules of the Immunoglobulin Superfamily Regulate Synapse Formation, Maintenance, and Function

Sytnyk, Vladimir; Leshchyns’ka, Iryna; Schachner, Melitta

doi:10.1016/j.tins.2017.03.003

Cited by 201 publications

(196 citation statements)

References 112 publications

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“…The immunoglobulin superfamily member L1 cell adhesion molecule is important for the development, plasticity, and repair of the nervous system, with multiple cellular functions, including notably its role in neurite outgrowth, neuronal cell migration, and survival, as well as myelination and synaptic plasticity [1,54]. The signaling pathways underlying L1-mediated neurite outgrowth and neuronal protection are well studied.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Neuronal Survival and Neurite Outgrowth Triggered by Novel Small Organic Compounds Mimicking the LewisX Glycan

et al. 2018

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Glycosylation fine-tunes signal transduction of adhesion molecules during neural development and supports synaptic plasticity and repair after injury in the adult nervous system. One abundantly expressed neural glycan is LewisX (LeX). Although it is known that its expression starts at the formation of the neural tube during the second embryonic week in the mouse and peaks during the first postnatal week, its functional relevance is only rudimentarily understood. To gain better insights into the functions of this glycan, we identified small organic compounds that mimic structurally and functionally this glycan glycosidically linked to several neural adhesion molecules. Mimetic compounds were identified by competitive enzyme-linked immunosorbent assay (ELISA) using the LeX-specific monoclonal antibodies L5 and SSEA-1 for screening a library of small organic molecules. In this assay, antibody binding to substrate-coated LeX glycomimetic peptide is measured in the presence of compounds, allowing identification of molecules that inhibit antibody binding and thereby mimic LeX. Gossypol, orlistat, ursolic acid, folic acid, and tosufloxacin inhibited antibody binding in a concentration-dependent manner. With the aim to functionally characterize the molecular consequences of the compounds' actions, we here present evidence that, at nM concentrations, the mimetic compounds enhance neurite outgrowth and promote neuronal survival of cultured mouse cerebellar granule cells via, notably, distinct signal transduction pathways. These findings raise hopes that these LeX mimetics will be powerful tools for further studying the functions of LeX and its effects in acute and chronic nervous system disease models. It is worth mentioning in this context that the LeX compounds investigated in the present study have been clinically approved for different therapies.

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Section: Discussionmentioning

confidence: 99%

Enhanced Neuronal Survival and Neurite Outgrowth Triggered by Novel Small Organic Compounds Mimicking the LewisX Glycan

et al. 2018

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“…Ig/FNIII proteins are classified as cell adhesion molecule (CAM) members of the immunoglobulin superfamily, and play prominent roles in neurodevelopment (Sytnyk et al, 2017). A number of proteins with similar domains are specifically involved in lumen formation: Neogenin, a Netrin receptor in the zebrafish, promotes neural tube formation (Mawdsley et al, 2004); Neuroglian , the Drosophila L1-CAM homolog, promotes formation of glial canals of the antennal lobe (Chen and Hing, 2008); and Robo, the Slit receptor, promotes formation of astrocytic tunnels leading to the olfactory bulb in mice (Kaneko et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

IGDB-2, an Ig/FNIII protein, binds the ion channel LGC-34 and controls sensory compartment morphogenesis in C. elegans

Wang

Perens

Oikonomou

et al. 2017

Developmental Biology

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Sensory organ glia surround neuronal receptive endings (NREs), forming a specialized compartment important for neuronal activity, and reminiscent of glia-ensheathed synapses in the central nervous system. We previously showed that DAF-6, a Patched-related protein, is required in glia of the C. elegans amphid sensory organ to restrict sensory compartment size. LIT-1, a Nemo-like kinase, and SNX-1, a retromer component, antagonize DAF-6 and promote compartment expansion. To further explore the machinery underlying compartment size control, we sought genes whose inactivation restores normal compartment size to daf-6 mutants. We found that mutations in igdb-2, encoding a single-pass transmembrane protein containing Ig-like and fibronectin type III domains, suppress daf-6 mutant defects. IGDB-2 acts in glia, where it localizes to glial membranes surrounding NREs, and, together with LIT-1 and SNX-1, regulates compartment morphogenesis. Immunoprecipitation followed by mass spectrometry demonstrates that IGDB-2 binds to LGC-34, a predicted ligand-gated ion channel, and lgc-34 mutations inhibit igdb-2 suppression of daf-6. Our findings reveal a novel membrane protein complex and suggest possible mechanisms for how sensory compartment size is controlled.

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“…The neural cell adhesion molecule (NCAM) is a membrane-bound cell recognition molecule of the immunoglobulin superfamily. NCAM contributes to the nervous system development by influencing neuronal migration, neurite outgrowth, synapse formation, and synaptic plasticity (Sytnyk et al, 2017). Alternative splicing of NCAM transcripts generates three major isoforms: NCAM180, NCAM140, and NCAM120.…”

Section: Introductionmentioning

confidence: 99%

NCAM regulates temporal specification of neural progenitor cells via profilin2 during corticogenesis

Huang

Yuan

et al. 2019

Journal of Cell Biology

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The development of cerebral cortex requires spatially and temporally orchestrated proliferation, migration, and differentiation of neural progenitor cells (NPCs). The molecular mechanisms underlying cortical development are, however, not fully understood. The neural cell adhesion molecule (NCAM) has been suggested to play a role in corticogenesis. Here we show that NCAM is dynamically expressed in the developing cortex. NCAM expression in NPCs is highest in the neurogenic period and declines during the gliogenic period. In mice bearing an NPC-specific NCAM deletion, proliferation of NPCs is reduced, and production of cortical neurons is delayed, while formation of cortical glia is advanced. Mechanistically, NCAM enhances actin polymerization in NPCs by interacting with actin-associated protein profilin2. NCAM-dependent regulation of NPCs is blocked by mutations in the profilin2 binding site. Thus, NCAM plays an essential role in NPC proliferation and fate decision during cortical development by regulating profilin2-dependent actin polymerization.

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Neural Cell Adhesion Molecules of the Immunoglobulin Superfamily Regulate Synapse Formation, Maintenance, and Function

Cited by 201 publications

References 112 publications

Enhanced Neuronal Survival and Neurite Outgrowth Triggered by Novel Small Organic Compounds Mimicking the LewisX Glycan

Enhanced Neuronal Survival and Neurite Outgrowth Triggered by Novel Small Organic Compounds Mimicking the LewisX Glycan

IGDB-2, an Ig/FNIII protein, binds the ion channel LGC-34 and controls sensory compartment morphogenesis in C. elegans

NCAM regulates temporal specification of neural progenitor cells via profilin2 during corticogenesis

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