Targeted mutation of Ncam to produce a secreted molecule results in a dominant embryonic lethality.

Rabinowitz, Joseph E.; Rutishauser, Urs; Magnuson, Terry

doi:10.1073/pnas.93.13.6421

Cited by 50 publications

(27 citation statements)

References 19 publications

(15 reference statements)

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“…Although the biological significance of NCAM heterophilic binding remains to be established, two HSPGs with interesting developmental expression patterns, namely agrin and the 6C4 antigen (21)(22)(23), have been shown to serve as heterophilic receptors for NCAM (15,16,24). Furthermore, the lethality of soluble NCAM produced in transgenic mice is most consistent with its interaction with a non-NCAM receptor (25).…”

mentioning

confidence: 78%

A Role for Polysialic Acid in Neural Cell Adhesion Molecule Heterophilic Binding to Proteoglycans

Storms¹,

Rutishauser²

1998

Journal of Biological Chemistry

107

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The neural cell adhesion molecule (NCAM) is known to participate in both homophilic and heterophilic binding, the latter including mechanisms that involve interaction with proteoglycans. The polysialic acid (PSA) moiety of NCAM can serve as a negative regulator of homophilic binding, but indirect evidence has suggested that PSA can also be involved in heterophilic binding. We have examined this potential positive role for PSA in terms of the adhesion of PSA-expressing mouse F11 cells and chick embryonic brain cells to substrates composed of the purified heparan sulfate proteoglycans agrin and 6C4. This adhesion was specifically inhibited by polyclonal anti-NCAM Fab antibodies, monoclonal anti-PSA antibodies, PSA itself, and enzymatic removal of either PSA or heparan sulfate side chains. By contrast, the adhesion was not affected by chondroitinase, and cell binding to laminin was not inhibited by any of these treatments. A specific NCAMheparan sulfate interaction in this adhesion was further indicated by its inhibition with monoclonal anti-NCAM Fab antibodies that recognize the known heparin-binding domain of NCAM and with the HBD-2 peptide derived from this region, but not with antibodies directed against other regions of the protein including the homophilic binding region. Together, the results suggest that PSA can act in vitro either as a receptor in NCAM heterophilic adhesion or as a promoter of binding between heparan sulfate proteoglycans and the NCAM heparin-binding domain.The most familiar and best characterized binding activity of the neural cell adhesion molecule (NCAM) 1 is as a homophilic receptor (1-4) primarily involving isologous interaction between NCAM Ig domain 3 on apposing cells (5-8). However, there is also ample evidence for two distinct heterophilic functions, one involving NCAM Ig domain 2 binding to certain heparan sulfate proteoglycans (HSPGs) (9 -16) and the other thought to involve binding of NCAM to the polypeptide core of the chondroitin sulfate proteoglycans neurocan and phosphacan (17)(18)(19)(20). Although the biological significance of NCAM heterophilic binding remains to be established, two HSPGs with interesting developmental expression patterns, namely agrin and the 6C4 antigen (21-23), have been shown to serve as heterophilic receptors for NCAM (15,16,24). Furthermore, the lethality of soluble NCAM produced in transgenic mice is most consistent with its interaction with a non-NCAM receptor (25).The possibility of multiple NCAM binding activities presents a challenge to the interpretation of NCAM perturbation and gene mutation studies, particularly in terms of molecular mechanism. One aspect of this ambiguity concerns the mode of action of the polysialic acid (PSA) moiety attached to NCAM. PSA has been proposed to function as a negative regulator of cell-cell interactions, possibly through steric effects stemming from its large size and abundance (26). Extensive evidence has been obtained both in vitro and in vivo to support this role and to establish its importance in promo...

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mentioning

confidence: 78%

A Role for Polysialic Acid in Neural Cell Adhesion Molecule Heterophilic Binding to Proteoglycans

Storms¹,

Rutishauser²

1998

Journal of Biological Chemistry

107

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“…as a soluble protein (36), and most recently, alterations reminiscent to schizophrenia were described in a conditional mouse model over-expressing soluble NCAM in late stages of neural development and in the adult (37). Including the current study, the animal models engineered to allow ectopic NCAM interactions prove impressively the importance of a strictly controlled NCAM homeostasis in the living system.…”

Section: Discussionmentioning

confidence: 99%

Genetic Ablation of Polysialic Acid Causes Severe Neurodevelopmental Defects Rescued by Deletion of the Neural Cell Adhesion Molecule

Weinhold

Seidenfaden

Röckle

et al. 2005

Journal of Biological Chemistry

267

270

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Poly-␣2,8-sialic acid (polySia) is a unique modification of the neural cell adhesion molecule, NCAM, tightly associated with neural development and plasticity. However, the vital role attributed to this carbohydrate polymer has been challenged by the mild phenotype of mice lacking polySia due to NCAM-deficiency. To dissect polySia and NCAM functions, we generated polySia-negative but NCAM-positive mice by simultaneous deletion of the two polysialyltransferase genes, St8sia-II and St8sia-IV. Beyond features shared with NCAM-null animals, a severe phenotype with specific brain wiring defects, progressive hydrocephalus, postnatal growth retardation, and precocious death was observed. These drastic defects were selectively rescued by additional deletion of NCAM, demonstrating that they originate from a gain of NCAM functions because of polySia deficiency. The data presented in this study reveal that the essential role of polySia resides in the control and coordination of NCAM interactions during mouse brain development. Moreover, this first demonstration in vivo that a highly specific glycan structure is more important than the glycoconjugate as a whole provides a novel view on the relevance of protein glycosylation for the complex process of building the vertebrate brain.The cellular glycosylation machinery is a most impressive example of how cells enhance structural and functional complexity by use of only limited parts (Ͻ10%) of the genome. Glycans conjugated to lipids and proteins form the glycocalyx, the outer rim and prominent communication structure of animal cells (1, 2). Their paramount importance is emphasized by the growing group of congenital disorders of glycosylation, which manifest as severe multisystemic diseases including neuropathological symptoms (3).Poly-␣2,8-linked sialic acid (polySia) 3 is a unique glycan added to the neural cell adhesion molecule, NCAM, and is known to exert an important influence on the development and function of the nervous system (4 -6). The intriguing role assigned to polySia in promoting neurogenesis, migration, axon outgrowth, and synaptic plasticity has been explained predominantly by a negative regulation of cell-cell interactions due to the stereochemical properties of the large polyanion (shown schematically in Fig. 1A) (4, 7). Recent x-ray and neutron reflectivity data as well as direct force measurements confirm that an increased intermembrane repulsion in the presence of polySia overcomes homophilic NCAM binding and attenuates cadherin-dependent adhesion (8, 9). On the other hand, polySia is known to exert highly specific functions. For instance, NCAM trans-interactions with heparan sulfate proteoglycans involved in the formation and remodeling of hippocampal synapses depend on the presence of polySia (10, 11). Finally, competition experiments carried out with exogenously added polySia indicate that the carbohydrate polymer mediates autonomous, NCAM-independent functions. These concern the development of commissural axons in zebrafish (12), the strengthening of ...

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“…The first indication for a potent heterophilic effect of NCAM came from mutant mice, which produce only secreted forms of NCAM and die during embryonic development (38). Transinteracting NCAM has been repeatedly reported to induce growth inhibition, but the significance of PSA for this process has never been addressed (5).…”

Section: Discussionmentioning

confidence: 99%

Polysialic Acid Directs Tumor Cell Growth by Controlling Heterophilic Neural Cell Adhesion Molecule Interactions

Seidenfaden

Krauter

Schertzinger

et al. 2003

Molecular and Cellular Biology

175

134

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Polysialic acid (PSA), a carbohydrate polymer attached to the neural cell adhesion molecule (NCAM), promotes neural plasticity and tumor malignancy, but its mode of action is controversial. Here we establish that PSA controls tumor cell growth and differentiation by interfering with NCAM signaling at cell-cell contacts. Interactions between cells with different PSA and NCAM expression profiles were initiated by enzymatic removal of PSA and by ectopic expression of NCAM or PSA-NCAM. Removal of PSA from the cell surface led to reduced proliferation and activated extracellular signal-regulated kinase (ERK), inducing enhanced survival and neuronal differentiation of neuroblastoma cells. Blocking with an NCAM-specific peptide prevented these effects. Combinatorial transinteraction studies with cells and membranes with different PSA and NCAM phenotypes revealed that heterophilic NCAM binding mimics the cellular responses to PSA removal. In conclusion, our data demonstrate that PSA masks heterophilic NCAM signals, having a direct impact on tumor cell growth. This provides a mechanism for how PSA may promote the genesis and progression of highly aggressive PSA-NCAM-positive tumors

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Targeted mutation of Ncam to produce a secreted molecule results in a dominant embryonic lethality.

Cited by 50 publications

References 19 publications

A Role for Polysialic Acid in Neural Cell Adhesion Molecule Heterophilic Binding to Proteoglycans

A Role for Polysialic Acid in Neural Cell Adhesion Molecule Heterophilic Binding to Proteoglycans

Genetic Ablation of Polysialic Acid Causes Severe Neurodevelopmental Defects Rescued by Deletion of the Neural Cell Adhesion Molecule

Polysialic Acid Directs Tumor Cell Growth by Controlling Heterophilic Neural Cell Adhesion Molecule Interactions

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