Elsevier

Progress in Neurobiology

Volume 80, Issue 3, October 2006, Pages 129-164
Progress in Neurobiology

PSA-NCAM in mammalian structural plasticity and neurogenesis

https://doi.org/10.1016/j.pneurobio.2006.08.003Get rights and content

Abstract

Polysialic acid (PSA) is a linear homopolymer of α2-8-N acetylneuraminic acid whose major carrier in vertebrates is the neural cell adhesion molecule (NCAM). PSA serves as a potent negative regulator of cell interactions via its unusual biophysical properties. PSA on NCAM is developmentally regulated thus playing a prominent role in different forms of neural plasticity spanning from embryonic to adult nervous system, including axonal growth, outgrowth and fasciculation, cell migration, synaptic plasticity, activity-induced plasticity, neuronal–glial plasticity, embryonic and adult neurogenesis. The cellular distribution, developmental changes and possible function(s) of PSA-NCAM in the central nervous system of mammals here are reviewed, along with recent findings and theories about the relationships between NCAM protein and PSA as well as the role of different polysialyltransferases. Particular attention is focused on postnatal/adult neurogenesis, an issue which has been deeply investigated in the last decade as an example of persisting structural plasticity with potential implications for brain repair strategies. Adult neurogenic sites, although harbouring all subsequent steps of cell differentiation, from stem cell division to cell replacement, do not faithfully recapitulate development. After birth, they undergo morphological and molecular modifications allowing structural plasticity to adapt to the non-permissive environment of the mature nervous tissue, that are paralled by changes in the expression of PSA-NCAM. The use of PSA-NCAM as a marker for exploring differences in structural plasticity and neurogenesis among mammalian species is also discussed.

Introduction

Cell adhesion systems should be regarded as molecular machineries that translate basic genetic information into complex three-dimensional patterns of cells in tissues (Gumbiner, 1996). Assembly of the central nervous system (CNS) architecture during development and maintenance of its circuitry throughout life are largely dependent on cell adhesion molecules (CAMs) capable of stabilizing and modulating cellular interactions. Several groups of molecules, belonging to the integrin, cadherin, immunoglobulin, and semaphorin superfamilies are involved in CNS morphogenesis and plasticity (for review see Walsh and Doherty, 1997, Hortsch, 2003, Hirano et al., 2003, Kruger et al., 2005).

Although the majority of CAMs are made up of a limited number of structural protein motifs (cadherin, immunoglobulin, fibronectin type III, semaphorin domains), their different number and arrangement leads to a variety of smaller subgroups. From an evolutionary point of view, this fact corresponds to an increase in the number of gene families which parallel the increasing complexity of nervous systems in animal species. As a result, today we find large CAM gene superfamilies and a molecular redundancy for CAM functions which have developed new protein–protein interactions (Hortsch, 2003). A wide range of possibilities involves homophilic adhesion (proteins interacting with their own), heterophilic adhesion (binding different ligands; reviewed in Kiselyov et al., 2005) or a combination of both mechanisms. Thus, besides the very narrow ligand specificity of certain CAMs others can interact with different ligands, either expressed on the cell surface (trans interactions if belonging to other cells, cis interactions if placed on the same cell membrane) or in the extracellular matrix. In addition, due to their connection with the cell cytoskeleton many CAMs provide a link between cell adhesion and cell structure, also intervening in the modulation of cellular signalling pathways (Gumbiner, 1996, Walsh and Doherty, 1997, Crossin and Krushel, 2000).

Among CAMs, the neural cell adhesion molecule (NCAM) is the most widely present and one among the most thoroughly studied molecules in the nervous system, whereby it is expressed on the surface of most cells (Hoffman et al., 1982, Edelman, 1986a, Edelman, 1986b). NCAM is a member of the immunoglobulin superfamily of adhesion molecules coded by a single copy gene composed of 26 exons (Edelman, 1986a, Edelman, 1986b, Goridis and Brunet, 1992, Rougon and Hobert, 2003). From the single copy gene of NCAM at least 20–30 distinct forms can be generated by alternative splicing and by post-translational modifications (Goridis and Brunet, 1992). Three main class sizes of 180, 140 and 120 kDa are generated by alternative splicing (Fig. 1). These three polypeptyde forms differ in their cytoplasmic domains (NCAM 180 and 140) or in their means of attachment to the cell membrane (NCAM 120), the latter having no cytoplasmic segment and being linked to the cell surface by a glycosylphosphatidylinositol intermediate (Edelman and Crossin, 1991; Fig. 1). The extracellular region of NCAM comprises five immunoglobulin (Ig1–5) and two fibronectin type III (Fn1–2) domains (Fig. 1). Studies on the crystal structure of the N-terminal domain of NCAM suggest that trans-cellular homophilic recognition and adhesion occur through dimerization of Ig1 and Ig2 domains from opposite cells which can form a cross-shaped antiparallel dimer (Kasper et al., 2000). A putative flexible, proline-rich hinge has been described between the fifth Ig domain and first fibronectin domain (Fig. 1). According to Johnson et al. (2004), a combination of multiple bound states and internal molecular flexibility allows for the ability to accomodate differences in intercellular spaces. NCAM establishes cell–cell adhesion through homophilic interactions of its extracellular domains. In addition, NCAM contains heparin (heparan sulfate)-binding domains. Indeed, although adhesion involves a homophilic binding mechanism, the binding of the cell surface proteoglycan heparan sulphate to the glycoprotein is also required (Cole et al., 1986).

Although adhesion is mainly devoted to the establishment of stable interactions within tissues, dynamic adhesive events also are of paramount importance for tissue development and subsequently in allowing structural plasticity (Gumbiner, 1996). Thus, after its crucial involvement in the assembly and stabilization of neural circuits, adhesion may play an important role in their maintenance and modulation, since the maintenance of stable connections may require active cellular processes, particularly in the nervous system. Under this profile, most of the interest linked to the widely studied NCAM has been prompted by the discovery that functional properties of this molecule are strongly influenced by polysialylation. Indeed, a sialic acid polymer can be added to all the three forms of NCAM by post-translational modification, thus introducing new possibilities of modulating adhesion.

Carbohydrates are important players in a variety of functions both in prokaryotic and eukaryotic cells (Kelm and Schauer, 1997, Breen et al., 1998, Kleene and Schachner, 2004). Polysialic acids are polymers of derivatives of nine carbon sugar neuraminic acids which can be found in a wide range of biological components: the coat of certain bacteria, the vitelline envelope of fish eggs, Drosophila embryos, membranes of vertebrate neural cells and of some cancer cells (reviewed in Rougon, 1993, Muhlenhoff et al., 1998). In mammals, they are typically found as terminal residues on the cell surface glycoconjugates, thus playing important roles in cellular recognition and adhesive processes. Unlike the large structural variability existing at the monomer level in fish and bacteria, polysialic acid (PSA) in mammals is a linear homopolymer of α2-8-linked N-acetylneuraminic acid (NeuNAc). PSA, added to NCAM by a regulated post-translational process, is a relatively simple and large molecule, the number of monomers ranging from about 8 to over 100 (Rougon, 1993, Rutishauser and Landmesser, 1996, Muhlenhoff et al., 1998). In solution this highly hydrated polyanion adopts a helical structure. The production of monoclonal antibodies which recognize 8–14 monomers have enabled the specific identification of this carbohydrate in extracts and tissue sections (Chuong et al., 1982, Frosch et al., 1985, Rougon et al., 1986, Sato et al., 1995; see below).

In 1982 (Finne), PSA was described as a major macromolecular component of vertebrate brains. Unlike most carbohydrates of the cell surface, PSA is attached exclusively to the NCAM (Finne et al., 1983, Hoffman et al., 1982, Acheson et al., 1991) as confirmed by its almost complete absence in NCAM-deficient mice (Tomasiewicz et al., 1993, Ono et al., 1994, Cremer et al., 1994). Polysialylation can account for up to 30% of relative molecular mass. The carbohydrate is added post-translationally and it is attached to two asparagines in the Ig5 module of the extracellular part of NCAM (Fig. 1). In eukaryotic cells the addition of PSA to NCAM occurs through two Golgi-associated polysialyltransferases: ST8SiaIV (PST) and ST8SiaII (STX) (Kitagawa and Paulson, 1994, Nakayama et al., 1995, Kojima et al., 1996, Eckhardt et al., 1995; reviewed in Angata and Fukuda, 2003). Sialic acids are synthesized in the cytosol from UDP-N-acetylglucosamine by four consecutive reactions, the key enzyme being the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine-kinase (GNE; Fig. 1). The activated sialic acid will then be used by polysialyltransferases to generate polysialylated NCAM within the Golgi (Alcaraz and Goridis, 1991, Bork et al., 2005). All sialyltransferases have a type II membrane protein topology as many Golgi-associated glycosyltransferases (Angata and Fukuda, 2003). The synthesis of PSA has been shown to occur on the cytoplasmic face of the inner membrane, requiring the polymer to traverse two lipid bilayers to reach the cell surface. The degree of polymerization of a PSA-containing glycopeptide fraction derived from brain tissue can be assessed by chemical methods (Inoue and Inoue, 2001). A cleavage of the PSA chains (degree of polymerization >5) can be experimentally obtained by using an endosialidase produced by a bacteriophage specific for Escherichia coli K1 (Endo-N, Vimr et al., 1984, Finne and Makela, 1985, Hallenbeck et al., 1987).

PSA-NCAM has been described to occur in different body tissues and organs, abundantly expressed during organogenesis (Lackie et al., 1990, Lackie et al., 1994, Fredette et al., 1993) and highly present in the nervous system (Finne, 1982, Hoffman et al., 1982, Rothbard et al., 1982, Chuong and Edelman, 1984). The expression of PSA is developmentally regulated by a combination of developmental or physiological programs, including its synthesis, delivery and degradation (reviewed in Bruses and Rutishauser, 2001). Several studies indicate that the two polysialyltransferases are expressed distinctly in a tissue- and cell-specific manner. In general, both enzymes are prevalently expressed during development, starting from E8–E9 in rodents, whereas they are downregulated in the adult (Kurosawa et al., 1997, Brocco et al., 2003). Although the level of STX declines dramatically after birth, that of PST gradually declines, and in the adult it is continuously expressed at lower levels in various tissues, even during adulthood (Eckhardt et al., 1995, Angata et al., 1997, Hildebrandt et al., 1998, Brocco et al., 2003). Both transcripts are detectable in adult brain areas undergoing continuous rearrangement and continuously expressing PSA (Phillips et al., 1997, Angata and Fukuda, 2003).

The amount of PSA on the cell surface probably depends upon two major regulatory mechanisms: (i) the synthesis of PSA-NCAM on the basis of transcription and/or activity of the sialyltransferases, and (ii) the turnover of the molecule at the cell surface (Kiss and Rougon, 1997). Biosynthesis of PSA-NCAM is regulated by cell activation (Kiss et al., 1994), such as electrical activity in axons, which can also influence its expression in the target cell (Fredette et al., 1993, Rafuse and Landmesser, 1996), or the loss of input from the periphery, as suggested by a model of unilateral dorsal rhizotomy in the rat (Bonfanti et al., 1996). The expression levels of polysialic acid can also be regulated by non-transcriptional ways, such as NMDA-evoked increase in the intracellular Ca2+ ions that can induce either exocytosis (Wang et al., 1996) or endocytosis (Bouzioukh et al., 2001a) of PSA-NCAM with increased expression or degradation, respectively. Although the activity of mammalian sialidases has not yet been fully understood, they are thought to be involved in cell differentiation, cell growth and malignant transformation (Miyagi et al., 2004). Different forms of endogenous murine sialidases (intralysosomal, cytosolic, lysosomal membrane and plasma membrane-associated) have been isolated, whose activity has been linked to invasiveness and metastatic abilty of tumors (reviewed in Miyagi et al., 2004). Finally, it has been recently proposed that polysialylation could be regulated by the biosynthesis of sialic acid at the GNE level (Bork et al., 2005).

Previous review articles focusing on polysialic acid structure, synthesis, and regulation of polysialylation are available (Rougon, 1993; Kiss and Rougon, 1997, Bruses and Rutishauser, 2001, Angata and Fukuda, 2003).

Section snippets

Distribution of PSA-NCAM in the nervous system

Since most analyses concerning the cellular and anatomical localization of PSA and NCAMs as well as most functional studies have been carried out on rodents, the following synthetic description will mainly focus on these species. Some comparative insight now available in several non-rodent mammals and other vertebrates will be reported if relevant to specific PSA-NCAM localizations and/or functions. In particular, the comparative issue relating to adult neurogenesis will be discussed in a

Mechanism(s) of PSA action

The classical view of PSA function refers to its ability to decrease NCAM-mediated membrane-membrane adhesion through its steric properties due to a high density of negative charges which contribute to the hydrated volume of NCAM (Rougon, 1993, Yang et al., 1994). The complex mechanism(s) allowing PSA to modulate NCAM-mediated cis, trans, homophilic and heterophilic interactions involve the effect of charge and hydration of the polymer, its influence on the width of extracellular spaces as well

The concept of structural plasticity in the nervous system

Two important features of the nervous system are specificity and plasticity (Zilles, 1992). Connectional, neurochemical and functional specificities are fundamental properties of CNS structure and hardwiring, which allow specific cell types to be connected and to act in a relatively invariant way (Frotscher, 1992). On the other hand, plasticity, namely the ability to make adaptive changes related to the structure and function of the nervous system (Bloom, 1985), must be considered another major

PSA-NCAM and postnatal/adult neurogenesis

Among different types of structural plasticity, the continuous production of new neural (neuronal and glial) cell precursors within the postnatal and adult CNS is the most striking exception to the dogma of a static nervous tissue composed of perennial elements (Gross, 2000). Theoretically, the activity of persistent neurogenic sites harbouring stem cell compartments does imply the existence of all types of structural plasticity typically working in the developing nervous system, including cell

PSA-NCAM, learning and memory

Experimental manipulations affecting the expression or the function of PSA-NCAM alter the ability of animals to learn (Becker et al., 1996, Cremer et al., 1994, O’Connell et al., 1997), as well as learning alters the expression of this molecule (Doyle et al., 1992, Fox et al., 1995b; Regan and Fox, 1995, Murphy et al., 1996).

Putting together several data reported in the previous sections concerning PSA-NCAM distribution in specific cell populations and systems, it may be noted that

PSA-NCAM and brain repair

Levels and distribution of polysialylation have been shown to increase or transiently change in several lesion/repair models, more frequently in association with neurite sprouting and reactive gliosis. Lesion-induced changes in PSA expression have also been observed in the modified activity of spontaneous neurogenic processes (reviewed in Romanko et al., 2004). Polysialylation is also involved in other pathological contexts which will be not reviewed here; for instance, PSA has a direct impact

Acknowledgements

This work was supported by MURST (F.I.R.B.), Compagnia di San Paolo (Progetto NEUROTRANSPLANT), Regione Piemonte, and University of Turin.

I wish to thank Dionysia Theodosis and Dominique Poulain for introducing me to the fascinating field of brain structural plasticity and for their support and fruitful discussions. I am also very grateful to Paolo Peretto, Giovanna Ponti, and Federico Luzzati for their contribution in experimental work.

References (389)

  • L. Bonfanti et al.

    Putative factors implicated in the structural plasticity of the hypothalamo-neurohypophysial system

    Regul. Pept.

    (1993)
  • L. Bonfanti et al.

    Dorsal rhizotomy induces transient expression of the highly sialylated isoform of the neural cell adhesion molecule in neurons and astrocytes of the adult spinal cord

    Neuroscience

    (1996)
  • L. Bonfanti et al.

    Newly-generated cells from the rostral migratory stream in the accessory ollfactory bulb of the adult rat

    Neuroscience

    (1997)
  • K. Bork et al.

    The intracellular concentration of sialic acid regulates the polysialylation of the neural cell adhesion molecule

    FEBS Lett.

    (2005)
  • P.A. Brennan et al.

    Neural mechanisms of mammalian olfactory learning

    Prog. Neurobiol.

    (1997)
  • J.L. Bruses et al.

    Roles, regulation, and mechanism of polysialic acid function during neural development

    Biochimie

    (2001)
  • J. Cai et al.

    Properties of a fetal multipotent neural stem cell (NEP cell)

    Dev Biol.

    (2002)
  • C.W. Cotman et al.

    Cell adhesion molecules in neural plasticity and pathology: similar mechanisms, distinct organizations?

    Prog. Neurobiol.

    (1998)
  • H. Cremer et al.

    NCAM is essential for axonal growth and fasciculation in the hippocampus

    Mol. Cell. Neurosci.

    (1997)
  • H. Cremer et al.

    PSA-NCAM: an important regulator of hippocampal plasticity

    Int. J. Dev. Neurosci.

    (2000)
  • L. Decker et al.

    Oligodendrocyte precursor migration and differentiation: combined effects of PSA residues, growth factors, and substrates

    Mol. Cell. Neurosci.

    (2000)
  • L. Decker et al.

    Loss of polysialic residues accelerates CNS neural precursor differentiation in pathological conditions

    Mol. Cell. Neurosci.

    (2002)
  • A. Dityatev et al.

    Synaptic strength as a function of post- versus presynaptic expression of the neural cell adhesion molecule NCAM

    Neuron

    (2000)
  • F. Doetsch et al.

    EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells

    Neuron

    (2002)
  • D. Fambrough et al.

    The Drosophila beaten path gene encodes a novel secreted protein that regulates defasciculation at motor axon choice points

    Cell

    (1996)
  • A. Acheson et al.

    NCAM polysialic acid can regulate both cell–cell and cell–substrate interactions

    J. Cell Biol.

    (1991)
  • G. Alcaraz et al.

    Biosynthesis and processing of polysialylated NCAM by AtT-20 cells

    Eur. J. Cell Biol.

    (1991)
  • G. Alonso

    Neuronal progenitor-like cells expressing polysialylated neural cell adhesion molecule are present on the ventricular surface of the adult rat brain and spinal cord

    J. Comp. Neurol.

    (1999)
  • G. Alonso et al.

    PSA-NCAM and B-50/GAP-43 are coexpressed by specific neuronal systems of the adult rat mediobasal hypothalamus that exhibit remarkable capacities for morphological plasticity

    J. Comp. Neurol.

    (1997)
  • J. Altman et al.

    Post-natal origin of microneurones in the rat brain

    Nature

    (1965)
  • P. Alvarez et al.

    Memory consolidation and the medial temporal lobe: a simple network model

    Proc. Natl. Acad. Sci. U.S.A.

    (1994)
  • A. Alvarez-Buylla et al.

    Neurogenesis in adult subventricular zone

    J. Neurosci.

    (2002)
  • J.A.J. Alves et al.

    Initial stages of radial glia astrocytic transformation in the early postnatal anterior subventricular zone

    J. Neurobiol.

    (2002)
  • A. Arvidsson et al.

    Neuronal replacement from endogenous precursors in the adult brain after stroke

    Nat. Med.

    (2002)
  • I. Aubert et al.

    Expression of L1 and PSA during sprouting and regeneration in the adult hippocampal formation

    J. Comp. Neurol.

    (1998)
  • D. Barbeau et al.

    Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains

    Proc. Natl. Acad. Sci. U.S.A.

    (1995)
  • M.-J. Barral-Moran et al.

    Oligodendrocyte progenitor migration in response to injury of glial monolayers requires the polysialic neural cell-adhesion molecule

    J. Neurosci. Res.

    (2003)
  • U. Bartsch et al.

    Highly sialylated N-CAM is expressed in adult mouse optic nerve and retina

    J. Neurocytol.

    (1990)
  • M. Bastmeyer et al.

    Dynamics of target recognition by interstitial axon branching along developing cortical axons

    J. Neurosci.

    (1996)
  • C.G. Becker et al.

    The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation

    J. Neurosci. Res.

    (1996)
  • A. Bédard et al.

    The rostral migratory stream in adult squirrel monkeys: contribution of new neurons to the olfactory tubercle and involvement of the antiapoptotic protein Bcl-2

    Eur. J. Neurosci.

    (2002)
  • A. Bédard et al.

    Chemical characterization of newly generated neurons in the striatum of adult primates

    Exp. Brain Res.

    (2005)
  • T. Ben-Hur et al.

    Growth and fate of PSA-NCAM+ precursors of the postnatal brain

    J. Neurosci.

    (1998)
  • P.J. Bernier et al.

    Newly generated neurons in the amygdala and adjoing cortex of adult primates

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • F.E. Bloom

    CNS plasticity: a survey of opportunities

  • S. Boisseau et al.

    Analysis of high PSA-NCAM expression during mammalian spinal cord and peripheral nervous system development

    Development

    (1991)
  • W. Bondareff et al.

    Distribution of the extracellular space during postnatal maturation of rat cerebral cortex

    Anat. Rec.

    (1968)
  • W. Bondareff et al.

    Age changes in the neuronal microenvironment

    Science

    (1972)
  • L. Bonfanti et al.

    Radial glia-like cells in the supraoptic nucleus of the adult rat

    J. Neuroendocrinol.

    (1993)
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