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

Abstract

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 ...

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility

“…38 In mouse models, regulation of glycan binding is required for most of the physiological functions of neuronal cell adhesion molecules, including brain morphogenesis, axonal trafficking and higher cognitive functioning. 39,40 The diversity of glycan functions is matched by a potentially vast array of hundreds, if not thousands, of potential structures. None of the overlapping risk alleles identified by this study map to genes previously implicated in psychosis.…”

L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

“…PSA attachment to NCAM globally regulates cellular responses to other factors by creating a permissive environment for cell migration. Deletion of PST and STX to prevent PSA attachment to NCAM inhibits the rostral migration of olfactory neuron precursors [30], and also affects both tangential and radial migration of cortical precursors, resulting in aberrant positioning of neuronal and glial cells [31]. PST/STX deficient mice also display more severe axonal defects than NCAM-deficient mice due to gain-of function effects [30].…”

“…Deletion of PST and STX to prevent PSA attachment to NCAM inhibits the rostral migration of olfactory neuron precursors [30], and also affects both tangential and radial migration of cortical precursors, resulting in aberrant positioning of neuronal and glial cells [31]. PST/STX deficient mice also display more severe axonal defects than NCAM-deficient mice due to gain-of function effects [30]. Premature removal of PSA from NCAM by endoglycosidase N treatment promotes synaptogenesis between GABAergic interneuron subpopulations and pyramidal cells in the visual cortex and regulates the onset of the critical period of visual plasticity in adolescence [32].…”

Polysialyltransferase expression is linked to neuronal migration in the developing and adult zebrafish

“…PSA synthesis on NCAM is specifically mediated by two polysialyltransferases, STX and PST, which act in a differential as well as synergistic manner Nakayama et al, 1998;Angata and Fukuda, 2003;Angata et al, 2004;Weinhold et al, 2005). Based on their differential expression PSA synthesis during embryogenesis has mainly been attributed to STX, whereas adult PSA synthesis is thought to be mediated preferentially by PST (Becker et al, 1996;Hildebrandt et al, 1998;Ong et al, 1998).…”