Morphoregulatory activities of NCAM and N-cadherin can be accounted for by G protein-dependent activation of L- and N-type neuronal Ca2+ channels

doi:10.1016/0092-8674(91)90569-K

Cell

Volume 67, Issue 1, 4 October 1991, Pages 21-33

https://doi.org/10.1016/0092-8674(91)90569-K Get rights and content

Abstract

We present evidence that the morphoregulatory activities of neural cell adhesion molecule (NCAM) and N-cadherin involve activation of intracellular second messenger pathways. PC12 cells were cultured on monolayers of control 3T3 cells or 3T3 cells expressing transfected N-cadherin or NCAM. NCAM and N-cadherin directly induced a transcription-independent change in the morphology of PC12 cells from an adrenal to neuronal phenotype and also specifically increased Thy-1, but not L1/NILE or low affinity NGF receptor, immunoreactivity. The morphological response was more rapid and, in the case of N-cadherin, more substantial than that induced by NGF. It could be fully inhibited by pertussis toxin and a combination of L- and N-type Ca²⁺ channel antagonists, but not by broad-specificity kinase inhibitors. It was blocked, however, bythe kinase inhibitor K-252b. These studies suggest that cell adhesion molecules directly alter cell phenotype and provide direct evidence for transmembrane signaling mediating both the morphological and biochemical responses induced by NCAM and N-cadherin.

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Functionally speaking, NCAD is essential in axonogenesis in vivo and mediates neurite outgrowth on astrocytes [54,78]. When PC12 cells were cultured on 3T3 fibroblast cell line that was transfected with chick NCAD [79], NCAD expression induced higher percentage of PC12 cells with neurites, together with longer neurite outgrowth length after 48 h. Furthermore, NCAD induced longer neurite outgrowth than soluble nerve growth factor (NGF), and a combination of NCAD and NGF increased neurite length synergistically [79]. Since NGF is commonly used in neural tissue engineering to enhance neurite outgrowth [80], better outcomes could possibly be achieved by combining with NCAD.
Neural tissue engineering holds great promise in repairing damaged nerve tissues. However, despite the promising results in regenerating the injured nervous system, tissue engineering approaches are still insufficient to result in full functional recovery in severe nerve damages. Majority of these approaches only focus on growth factors and cell-extracellular matrix (ECM) interactions. As another important component in nerve tissues, the potential of modulating cell-cell interactions as a strategy to promote regeneration has been overlooked. Within the central nervous system, there are considerably more cell-cell communications as compared to cell-ECM interactions, since the ECM only contributes 10%–20% of the total tissue volume. Therefore, modulating cell-cell interactions through cell adhesion molecules (CAMs) such as cadherins, neural cell adhesion molecules (NCAM) and L1, may be a potential alternative to improve nerve regeneration. This paper will begin by reviewing the CAMs that play important roles in neurogenic processes. Specifically, we focused on 3 areas, namely the roles of CAMs in neurite outgrowth and regeneration; remyelination; and neuronal differentiation. Following that, we will discuss existing tissue engineering approaches that utilize CAMs and biomaterials to control nerve regeneration. We will also suggest other potential methods that can deliver CAMs efficiently to injured nerve tissues. Overall, we propose that utilizing CAMs with biomaterials may be a promising therapeutic strategy for nerve regeneration.
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This interaction can subsequently regulate cell behavior such as: cell migration, proliferation, apoptosis and differentiation (Becchetti et al., 1992; Schwartz, 1993). A good example of this interaction is observed in PC12 cells whose shift to a neuronal phenotype is induced by the physical interaction of voltage-gated Ca2+ channels and neural cell adhesion molecules/N-cadherins (Doherty et al., 1991). Over the last several decades, numerous studies have demonstrated adhesive receptors (especially integrins) physically and functionally associated with several classes of ion channels (Arcangeli and Becchetti, 2006).
The ability to control pattern formation is critical for the both the embryonic development of complex structures as well as for the regeneration/repair of damaged or missing tissues and organs. In addition to chemical gradients and gene regulatory networks, endogenous ion flows are key regulators of cell behavior. Not only do bioelectric cues provide information needed for the initial development of structures, they also enable the robust restoration of normal pattern after injury. In order to expand our basic understanding of morphogenetic processes responsible for the repair of complex anatomy, we need to identify the roles of endogenous voltage gradients, ion flows, and electric fields. In complement to the current focus on molecular genetics, decoding the information transduced by bioelectric cues enhances our knowledge of the dynamic control of growth and pattern formation. Recent advances in science and technology place us in an exciting time to elucidate the interplay between molecular-genetic inputs and important biophysical cues that direct the creation of tissues and organs. Moving forward, these new insights enable additional approaches to direct cell behavior and may result in profound advances in augmentation of regenerative capacity.
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The cell–cell and cell–matrix interactions mediated by the adhesion molecules on the cell surface are vital to neural development and plasticity. The neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily, promotes cell-to-cell adhesion in the nervous system through a homophilic, Ca²⁺-independent binding mechanism. NCAM-mediated cell adhesion is involved in the regulation of neural cell migration, neurite outgrowth and fasciculation, and synaptic formation. Polysialic acid (PSA), found as a component of neural tissue, is a linear homopolymer containing sialic acid residues in -2,8-linkage. Polysialylation of the NCAM decreases the homophilic binding of NCAM thereby attenuating cell adhesion. The attachment of PSA to NCAM gives rise to additional mechanisms in modulating cell adhesion. The polysialylation of NCAM is modulated in the developmental stage and is site-specific during the development. Endoneuraminidase N, which specifically cleaves PSA without compromising the cell viability, has been utilized to explore the modulatory effects of PSA upon cell migration. PAS on the NCAM contributes to the motility of migratory cells. The expression levels of NCAM and polysialylated NCAM are critical for neural plasticity, which is dependent on either cell migration and sprouting or the synaptic activity.
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Cell Adhesion Molecules in Metal Neurotoxicity
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Cell

ArticleMorphoregulatory activities of NCAM and N-cadherin can be accounted for by G protein-dependent activation of L- and N-type neuronal Ca2+ channels

Abstract

Neuron

Neuron

Neuron

Curr. Opinion Cell Biol.

Exp. Cell Res.

Neurosci. Lett.

Neuron

Neuron

Dev. Biol.

Neurosci. Lett.

Trends Neurosci.

Dev. Biol.

Dev. Biol.

J. Biol. Chem.

Trends Neurosci.

Neuron

Neuron

Extracellular matrix molecules and cell adhesion molecules induce neurite through different mechanisms

J. Cell Biol.

Neurite outgrowth on muscle cell surfaces involves extracellular matrix receptors as well as Ca2+-dependent and -independent cell adhesion molecules

cAMP analog antagonists of cAMP action

Meth. Enzymol.

Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation and alternative splicing

Science

Timing and site of nerve growth factor synthesis in developing skin in relation to innervation and expression of the receptor

Nature

Skeletal muscle N-CAM: evidence for a role of myoblast fusion

Nature

Control of Thy-1 glycoprotein expression in cultures of PC12 cells

J. Neurochem.

Cell-cell interactions regulate the responsiveness of PC12 cells to nerve growth factor

Development

Comparison of the effects of NGF, activators of protein kinase C, and a calcium ionophore on the expression of Thy-1 and N-CAM in PC12 cell cultures

J. Cell Biol.

Neuronal process outgrowth of human sensory neurons on monolayers of cells transfected with cDNAs for five human NCAM isoforms

J. Cell Biol.

A threshold effect of the major isoforms of NCAM on neurite outgrowth

Nature

Article
Morphoregulatory activities of NCAM and N-cadherin can be accounted for by G protein-dependent activation of L- and N-type neuronal Ca²⁺ channels

Neurite outgrowth on muscle cell surfaces involves extracellular matrix receptors as well as Ca²⁺-dependent and -independent cell adhesion molecules