Polysialylation of the Neural Cell Adhesion Molecule: Setting the Stage for Plasticity Across Scales of Biological Organization

In vertebrates, the neuronal cell adhesion molecule (NCAM/CD56) has 3 isoforms resulting from alternative splicing that differ by their size (120, 140 and 180 kDa) and their anchoring at the membrane. Whereas NCAM120 is glycophosphatidyl inositol anchored, NCAM140 and NCAM180 are transmembrane molecules. NCAM180 has an additional intracellular 267 amino acids insert, that differentiate it from NCAM140, but its role remains to be fully elucidated. There are differences regarding the specificity and the level of expression of these isoforms in different cells of the nervous system. Whereas NCAM120 and NCAM140 are preferentially expressed in glial cells NCAM180 seems to be prevalent on neurons. Although differences in expression and function of the NCAM isoforms exist, one common denominator is that they can be post-translationally modified by the addition of long, linear chains of α2,8-linked Nacetylneuraminic acid (Neu5Ac) residues. In vertebrates, NCAM is the major acceptor of this unique carbohydrate. This modification occurs on the fifth immunoglobulin domain of NCAM located on the extracellular part of the membrane and common to all 3 isoforms. These polysialylated isoforms have emerged as particularly attractive candidates for promoting plasticity in the central nervous system (CNS). The large negatively charged polysialic acid (PSA) chain of NCAM is postulated to be a spacer that reduces adhesion forces between cells allowing dynamic changes in membrane contacts. However, recent studies indicate that a crucial function of PSA resides in controlling interactions mediated by NCAM. Accumulating evidence also suggests that PSA-NCAM-mediated interactions lead to activation of intracellular signals fundamental to biological functions. An important role of PSA-NCAM appears to be during development, when its expression level is high and where it contributes to the regulation of cell shape, growth or migration. However, PSA-NCAM does persist in adult brain structures such as the hippocampus that display a high degree of plasticity where