Polysialic acid (PSA) is a cell-surface glycan with an enormous hydrated volume that serves to modulate the distance between cells. This regulation has direct effects on several cellular mechanisms that underlie the formation of the vertebrate nervous system, most conspicuously in the migration and differentiation of progenitor cells and the growth and targeting of axons. PSA is also involved in a number of plasticity-related responses in the adult CNS, including changes in circadian and hormonal patterns, adaptations to pain and stress, and aspects of learning and memory. The ability of PSA to increase the plasticity of neural cells is being exploited to improve the repair of adult CNS tissue.
The neural cell adhesion molecule (NCAM) can influence a number of diverse intercellular events, including junctional communication, the association of axons with pathways and targets, and signals that alter levels of neurotransmitter enzymes. These pleiotropic effects appear to reflect the ability of NCAM to regulate membrane-membrane contact required to initiate specific interactions between other molecules. Such regulation can occur through changes in either NCAM expression or the molecule's content of polysialic acid (PSA). When NCAM with a low PSA content is expressed, adhesion is increased and contact-dependent events are triggered. In contrast, the large excluded volume of NCAM PSA can inhibit cell-cell interactions through hindrance of overall membrane apposition.
Abstract.-The complete amino acid sequence of a human yG1 immunoglobulin (Eu) has been determined and the arrangement of all of the disulfide bonds has been established. Comparison of the sequence with that of another myeloma protein (He) suggests that the variable regions of heavy and light chains are homologous and similar in length. The constant portion of the heavy chain contains three homology regions each of which is similar in size and homologous to the constant region of the light chain. Each variable region and each constant homology region contains one intrachain disulfide bond. The half-cystines participating in the interchain bonds are all clustered within a stretch of ten residues at the middle of the heavy chains.These data support the hypothesis that immunoglobulins evolved by gene duplication after early divergence of V genes, which specified antigen-binding functions, and C genes, which specified other functions of antibody molecules. Each polypeptide chain may therefore be specified by two genes, V and C, which are fused to form a single gene (translocation hypothesis). The internal homologies and symmetry of the molecule suggest that homology regions may have similar three-dimensional structures each consisting of a compact domain which contributes to at least one active site (domain hypothesis). Both hypotheses are in accord with the linear regional differentiation of function in antibody molecules.Antibodies or immunoglobulins can interact with a wide range of different antigenic determinants and, after specific binding to an antigen, they play a fundamental part in physiological functions of the immune response. The specificity of antigen binding depends ultimately upon amino acid sequences of the variable or V regions of antibody molecules. It is the diversity of these sequences which results in the range of specificities required for a selective immune response. In contrast, other regions of the antibody molecule have relatively constant sequences and are responsible for physiological functions. Like enzymes, these C regions appear to have evolved for a restricted set of interactions. This unusual picture of intramolecular differentiation has emerged from studies of the structure of immunoglobulins from different animal species.' To date, only portions of immunoglobulin molecules have been subjected to amino acid sequence determination.We now report the amino acid sequence of an entire human 'yG1 immunoglobulin (molecular weight 150,000), the location of all disulfide bonds, the arrangement of light and heavy chains, and the length of the heavy chain V region.78
Transplantation studies have been used to show that tangential migration of olfactory bulb interneuron precursors is retarded in NCAM-mutant mice, and that this defect reflects loss of NCAM polysialic acid (PSA). In contrast, radial migration of cells within the bulb did not require PSA. Reciprocal transplantations between wild-type and mutant mice have revealed that the mutation affects the in vivo migration environment in the subventricular zone, and not movement of individual cells. However, in vitro migration of the cells into a PSA-negative collagen matrix environment was also PSA dependent. The surprisingly similar results obtained in the in vivo and in vitro environments is consistent with the observation that migration of subventricular cells occurs as streams of closely apposed cells in which the PSA-positive cells appear to serve as their own migration substrate.
N-CAM, the neural cell adhesion molecule, has been found at a number of regions in the early (1-5 days) chicken embryo by fluorescent antibody techniques. These regions appear to be those concerned with induction of the primary developmental axis (neural plate, neural tube, notochord, somites) or those in which later inductive events occur (neural crest cells, optic, otic, and pharyngeal placodes, cardiac mesoderm, mesonephric primordium, limb buds). The staining patterns in the latter group of regions are highly dynamic and transient and are limited to the epithelial components of the placodes and to the precursors of mesonephric tubules. In neural crest cells, N-CAM appears early, disappears during migration of the cells on fibronectin, and reappears at sites where ganglia are formed. In other regions of the nervous system, particularly those related directly to the neural tube, the N-CAM molecule is stained at all stages. The results raise the possibility that adhesion mediated by N-CAM plays a primary role in early embryogenesis as well as in later histogenesis.
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