多聚唾液酸与多聚唾液酸转移酶

多聚唾液酸（PSA）是一种在神经细胞黏附分子（neural cell adhesion molecule,NCAM）上表达的唾液酸聚合物,在神经发育过程中起重要作用.PSA的聚合程度会影响PSA-NCAM的功能.多聚唾液酸酶主要用于合成PSA-NCAM,两种高度同源的多聚唾液酸转移酶ST8SiaⅡ和ST8SiaⅣ都属于唾液酸转移酶家族.多聚唾液酸转移酶中NCAM的识别域和多聚唾液酸化域是截然不同的,且一些异构酶在NCAM多聚唾液酸化中起明显的负作用.多聚唾液酸酶与很多疾病都有关系,以多聚唾液酸转移酶为标靶设计的药物也将成为神经系统及肿瘤治疗的新型药物.     

Polysialic and colanic acids metabolism in Escherichia coli K92 is regulated by RcsA and RcsB

We have shown previously that Escherichia coli K92 produces two different capsular polymers known as CA (colanic acid) and PA (polysialic acid) in a thermoregulated manner. The complex Rcs phosphorelay is largely related to the regulation of CA synthesis. Through deletion of rscA and rscB genes, we show that the Rcs system is involved in the regulation of both CA and PA synthesis in E. coli K92. Deletion of either rcsA or rcsB genes resulted in decreased expression of cps (CA biosynthesis cluster) at 19°C and 37°C, but only CA production was reduced at 19°C. Concerning PA, both deletions enhanced its synthesis at 37°C, which does not correlate with the reduced kps (PA biosynthesis cluster) expression observed in the rcsB mutant. Under this condition, expression of the nan operon responsible for PA catabolism was greatly reduced. Although RcsA and RcsB acted as negative regulators of PA synthesis at 37°C, their absence did not reestablish PA expression at low temperatures, despite the deletion of rcsB resulting in enhanced kps expression. Finally, our results revealed that RcsB controlled the expression of several genes (dsrA, rfaH, h-ns and slyA) involved in the thermoregulation of CA and PA synthesis, indicating that RcsB is part of a complex regulatory mechanism governing the surface appearance in E. coli.     

Polysialic acid and activity-dependent synapse remodeling

Polysialic acid (PSA) is a large carbohydrate added post-translationally to the extracellular domain of the Neural Cell Adhesion Molecule (NCAM) that influences its adhesive and other functional properties. PSA-NCAM is widely distributed in the developing nervous system where it promotes dynamic cell interactions, like those responsible for axonal growth, terminal sprouting and target innervation. Its expression becomes restricted in the adult nervous system where it is thought to contribute to various forms of neuronal and glial plasticity. We here review evidence, obtained mainly from hypothalamic neuroendocrine centers and the olfactory system, that it intervenes in structural synaptic plasticity and accompanying neuronal-glial transformations, making possible the formation and elimination of synapses that occur under particular physiological conditions. While the mechanism of action of this complex sugar is unknown, it is now clear that it is a necessary molecular component of various cell transformations, including those responsible for activity-dependent synaptic remodeling.Key words: adhesion, synaptic plasticity, astrocytes, central nervous system, hypothalamus, olfactory system     

Polysialic acid and activity-dependent synapse remodeling

Polysialic acid (PSA) is a large carbohydrate added post-translationally to the extracellular domain of the Neural Cell Adhesion Molecule (NCAM) that influences its adhesive and other functional properties. PSA-NCAM is widely distributed in the developing nervous system where it promotes dynamic cell interactions, like those responsible for axonal growth, terminal sprouting and target innervation. Its expression becomes restricted in the adult nervous system where it is thought to contribute to various forms of neuronal and glial plasticity. We here review evidence, obtained mainly from hypothalamic neuroendocrine centers and the olfactory system, that it intervenes in structural synaptic plasticity and accompanying neuronal-glial transformations, making possible the formation and elimination of synapses that occur under particular physiological conditions.     

Polysialic acid-based micelles for encapsulation of hydrophobic drugs

Despite improvements relative to unmodified counterparts, poly(ethylene glycol) (PEG) conjugation may not be the ideal solution for improving circulatory stability of current nanoparticle carriers or free drugs. Polysialic acid (PSA), a natural polymer for which the body possesses no receptors, has been conjugated directly to biologically active molecules to prevent premature clearance; however, this concept has not yet been applied to nanoparticle drug carrier systems. In the current study, PSA was modified with a long-chain hydrocarbon through reaction of the carboxylic acid side groups with N-decylamine (DA). The resultant PSA-DA conjugates self-assembled into micelles for encapsulation of hydrophobic drug molecules, as demonstrated with Cyclosporine A. Cytotoxicty was dependent on the degree of substitution with DA. On the basis of size and zeta potential, the micelles are capable of passively targeting diseased regions, such as cancer and inflammatory tissue. Further investigations are necessary to explore whether the PSA-based micelles possess stealth properties similar to those of PEG and to establish in vitro and in vivo efficacy.     

Polysialic acid facilitates tumor invasion by glioma cells

Polysialic acid (PSA) is thought to attenuate neural cell adhesion molecule (NCAM) adhesion, thereby facilitating neural cell migration and regeneration. Although the expression of PSA has been shown to correlate with the progression of certain tumors such as small cell lung carcinoma, there have been no studies to determine the roles of PSA in gliomas, the most common type of primary brain tumor in humans. In this study, we first revealed that among patients with glioma, PSA was detected more frequently in diffuse astrocytoma cells, which spread extensively. To determine directly the role of PSA in glioma cell invasion, we transfected C6 glioma cells with polysialyltransferases to express PSA. In those transfected cells, PSA is attached mainly to NCAM-140, whereas the mock-transfected C6 cells express equivalent amounts of PSA-free NCAM-140. Both PSA negative and positive C6 cell lines exhibited almost identical growth rates measured in vitro. However, PSA positive C6 cells exhibited increased invasion to the corpus callosum, where the mock-transfected C6 glioma cells rarely invaded when inoculated into the brain. By contrast, the invasion to the corpus callosum by both the mock-transfected and PSA positive C6 cells was observed in NCAM-deficient mice. These results combined indicate that PSA facilitates tumor invasion of glioma in the brain, and that NCAM-NCAM interaction is likely attenuated in the PSA-mediated tumor invasion.     

Polysialic acid influences specific pathfinding by avian motoneurons.

The influence of polysialic acid (PSA) on the neural cell adhesion molecule on motoneuron outgrowth and pathway formation was investigated by determining its temporal and spatial pattern of expression and by the effect that its removal had on motoneuron projection patterns. Motoneurons first expressed PSA as their growth cones began to segregate into motoneuron pool-specific groups in the plexus region; furthermore, PSA levels differed between motoneurons projecting to different targets. When PSA was removed during the period of axonal segregation in the plexus region projection errors were common. However, later removal during the process of muscle nerve formation did not result in projection errors. These results suggest that PSA modulates interactions between motoneuron axons and guidance molecules in the plexus region during axonal pathfinding.     

Polysialic Acids: Potential Role in Therapeutic Constructs

Abstract

Prokaryotic microorganisms are widespread in all environments on Earth, establishing diverse interactions with many eukaryotic taxa, including insects. These associations may be symbiotic, pathogenic and vectoring. Independently of the type of interaction, each association starts with the adhesion of the microorganism to the host, entry and “invasion” of the host, then progresses to establishment and dissemination within the host, by avoiding host immune responses, and concludes with transmission back to the environment or to a new host. Advances in genomics and genetics have allowed the dissection of these processes and provided important information on the elements driving the shaping of the members of each association. Furthermore, many mechanisms involved in the establishment of the associations have been scrutinised, along with the development of new methods for the management of insect populations.     

Polysialic acid can mediate membrane interactions by interacting with phospholipids

Polysialic acid (polySia) is expressed on the surface of neural cells, neuroinvasive bacterial cells and several tumor cells. PolySia chains attached to NCAM can influence both trans interactions between membranes of two cells and cis interactions. Here, we report on the involvement of phospholipids in regulation of membrane interactions by polySia. The pH at the surface of liposomes, specific molecular area of phosphatidylcholine molecules, phase transition of DPPC bilayers, cyclic voltammograms of BLMs, and electron micrographs of phosphatidylcholine vesicles were studied after addition of polysialic acid free in solution. The results indicate that polySia chains can associate with phosphatidylcholine bilayers, incorporate into the polar part of a phospholipid monolayer, modulate cis interactions between phosphatidylcholine molecules, and facilitate trans interactions between apposing phospholipid vesicles. These observations imply that polySia attached to NCAM or to lipids can behave similarly.     

Polysialic acid: Biosynthesis,novel functions and applications

Abstract

As an anti-adhesive, a reservoir for key biological molecules, and a modulator of signaling, polysialic acid (polySia) is critical for nervous system development and maintenance, promotes cancer metastasis, tissue regeneration and repair, and is implicated in psychiatric diseases. In this review, we focus on the biosynthesis and functions of mammalian polySia, and the use of polySia in therapeutic applications. PolySia modifies a small subset of mammalian glycoproteins, with the neural cell adhesion molecule, NCAM, serving as its major carrier. Studies show that mammalian polysialyltransferases employ a unique recognition mechanism to limit the addition of polySia to a select group of proteins. PolySia has long been considered an anti-adhesive molecule, and its impact on cell adhesion and signaling attributed directly to this property. However, recent studies have shown that polySia specifically binds neurotrophins, growth factors, and neurotransmitters and that this binding depends on chain length. This work highlights the importance of considering polySia quality and quantity, and not simply its presence or absence, as its various roles are explored. The capsular polySia of neuroinvasive bacteria allows these organisms to evade the host immune response. While this “stealth” characteristic has made meningitis vaccine development difficult, it has also made polySia a worthy replacement for polyetheylene glycol in the generation of therapeutic proteins with low immunogenicity and improved circulating half-lives. Bacterial polysialyltransferases are more promiscuous than the protein-specific mammalian enzymes, and new studies suggest that these enzymes have tremendous therapeutic potential, especially for strategies aimed at neural regeneration and tissue repair.     

两阶段搅拌转速控制策略发酵生产聚唾液酸

目的:优化聚唾液酸发酵过程的搅拌转速.方法:比较不同搅拌转速对大肠杆菌Escherichia coli K235分批发酵生产聚唾液酸过程的影响.结果:根据发酵前、后期菌体细胞比生长速率和聚唾液酸比合成速率达到最大值所需搅拌转速的不同,提出了两阶段搅拌转速控制策略:发酵前期(0～15h)控制搅拌转速500r/min,发酵中后期控制搅拌转速700r/min.结论:两阶段搅拌转速控制策略使聚唾液酸产量达到3 966mg/L,比恒定搅拌转速500r/min和700r/min分别提高了31.8%和49.3%.将两阶段搅拌转速控制策略与分批补料发酵技术结合,聚唾液酸产量提高到5 108mg/L,山梨醇的转化率达到0.12g/g.     

Polysialic acid chains exhibit enhanced affinity for ordered regions of membranes

Polysialic acid (polySia) forms linear chains which are usually attached to the external surface of the plasma membrane mainly through the Neural Cell Adhesion Molecule (NCAM) protein. It is exposed on neural cells, several types of cancer cells, dendritic cells, and egg and sperm cells. There are several lipid raft-related phenomena in which polySia is involved; however the mechanisms of polySia action as well as determinants of its localization in lipid raft microdomains are still unknown, although the majority of NCAM molecules in the liquid-ordered raft membrane fractions of neural cells appear to be polysialylated. Here we investigate the affinity of polySia (both soluble and NCAM-dependent plasma membrane-bound) for liquid-ordered- and liquid-disordered regions of lipid vesicle and neuroblastoma cell membranes. Our studies indicate that polySia chains have a higher affinity for ordered regions of membranes as determined by the dissociation constant values for polySia-lipid bilayer complex, the fluorescence intensity of polySia bound to giant vesicles, the polySia-to-membrane FRET signal at the plasma membrane of live cells, and the decrease of the FRET signals after Endo-N treatment of the cells. These results suggest that polysialylation may be one of the determinants of protein association with liquid-ordered membrane lipid raft domains.     

Polysialic acid limits choline acetyltransferase activity induced by brain-derived neurotrophic factor

Choline acetyltransferase (ChAT), the enzyme synthesizing acetylcholine, is known to be activated by brain derived neurotrophic factor (BDNF). We found that the specific removal of the carbohydrate polysialic acid (PSA) significantly increased BDNF-induced ChAT-activity in embryonic septal neurons. Using a p75 neurotrophin receptor (p75(NTR)) function-blocking antibody and K252a, a-pan tropomyosin related kinase (Trk) inhibitor, we demonstrate that BDNF-induced ChAT activity requires the stimulation of p75(NTR) and TrkB. PSA removal drastically increased radioactive iodinated ([(125)I])BDNF's maximal binding capacity (Bmax), derived from concentrations of [(125)I]BDNF ranging from 1 pM to 3.2 nM. In the presence of unlabeled nerve growth factor to prevent the binding of [(125)I]BDNF to p75(NTR) sites, the impact of PSA removal on the binding capacity of [(125)I]BDNF was greatly reduced. In conclusion, PSA limits BDNF-induced ChAT activity and BDNF-receptor interactions. BDNF-induced ChAT activity is TrkB and p75(NTR) dependent, and upon PSA removal the additional binding of BDNF to its receptors, especially p75(NTR), likely contributes to the maximal ChAT activity observed. In vivo, the ontogenetic loss of PSA in the postnatal period may allow more interactions between BDNF and its receptors to increase ChAT activity and assure the proper development of the cholinergic septal neurons.     

Polysialic acid as a regulator of intramuscular nerve branching during embryonic development

The role of polysialic acid (PSA) during initial innervation of chick muscle was examined. Previously, the adhesion molecules L1 and N-CAM were shown to be important in balancing axon-axon and axon-muscle adhesion during this process. Here we demonstrate developmental changes in the pattern of innervation that are not correlated with levels of L1 or N-CAM expression, but rather with the amount of PSA at the axon surface. Removal of PSA by a specific endoneuraminidase (Endo-N) increased axon fasciculation and reduced nerve branching. In contrast, the nerve trunk defasciculation and increased branching produced by neuromuscular activity blockade were associated with an increase in axonal PSA levels. Furthermore, Endo-N prevented these inactivity-induced effects on branching. Together these results illustrate the potential of PSA as a regulator of cell-cell interactions and provide a direct example of a molecular link between the morphogenic effects of adhesion-mediated and synaptic activity-dependent processes.     

Polysialic acid bioengineering of neuronal cells by N-acyl sialic acid precursor treatment

The inherent promiscuity of the polysialic acid (PSA) biosynthetic pathway has been exploited by the use of exogenous unnatural sialic acid precursor molecules to introduce unnatural modifications into cellular PSA, and has found applications in nervous system development and tumor vaccine studies. The sialic acid precursor molecules N-propionyl- and N-butanoyl-mannosamine (ManPr, ManBu) have been variably reported to affect PSA biosynthesis ranging from complete inhibition to de novo production of modified PSA, thus illustrating the need for further investigation into their effects. In this study, we have used a monoclonal antibody (mAb) 13D9, specific to both N-propionyl-PSA and N-butanoyl-PSA (NPrPSA and NBuPSA), together with flow cytometry, to study precursor-treated tumor cells and NT2 neurons at different stages of their maturation. We report that both ManPr and ManBu sialic acid precursors are metabolized and the resultant unnatural sialic acids are incorporated into de novo surface sialylglycoconjugates in murine and human tumor cells and, for the first time, in human NT2 neurons. Furthermore, neither precursor treatment deleteriously affected endogenous PSA expression; however, with NT2 cells, PSA levels were naturally downregulated as a function of their maturation into polarized neurons independent of sialic acid precursor treatment.     

Structural and Kinetic Characterizations of the Polysialic Acid O-Acetyltransferase OatWY from Neisseria meningitidis

The neuroinvasive pathogen Neisseria meningitidis has 13 capsular serogroups, but the majority of disease is caused by only 5 of these. Groups B, C, Y, and W-135 all display a polymeric sialic acid-containing capsule that provides a means for the bacteria to evade the immune response during infection by mimicking host sialic acid-containing cell surface structures. These capsules in serogroups C, Y, and W-135 can be further acetylated by a sialic acid-specific O-acetyltransferase, a modification that correlates with decreased immunoreactivity and increased virulence. In N. meningitidis serogroup Y, the O-acetylation reaction is catalyzed by the enzyme OatWY, which we show has clear specificity toward the serogroup Y capsule ([Glc-(α1→4)-Sia]_n). To understand the underlying molecular basis of this process, we have performed crystallographic analysis of OatWY with bound substrate as well as determined kinetic parameters of the wild type enzyme and active site mutants. The structure of OatWY reveals an intimate homotrimer of left-handed β-helix motifs that frame a deep active site cleft selective for the polysialic acid-bearing substrate. Within the active site, our structural, kinetic, and mutagenesis data support the role of two conserved residues in the catalytic mechanism (His-121 and Trp-145) and further highlight a significant movement of Tyr-171 that blocks the active site of the enzyme in its native form. Collectively, our results reveal the first structural features of a bacterial sialic acid O-acetyltransferase and provide significant new insight into its catalytic mechanism and specificity for the capsular polysaccharide of serogroup Y meningococci.The bacterial pathogen Neisseria meningitidis is a major cause of life-threatening neuroinvasive meningitis in humans (1). In the United States, 75% of bacterial meningitis infections are caused by serogroup C, Y, or W-135 (2). In particular, the proportion of meningococcal infection occurrences in the United States caused by the group Y meningococci has increased significantly from 2% during 1989–1991 to 37% during 1997–2002 (2). Vaccines based on the capsular polysaccharide have been developed for groups A/C/Y/W-135 (2), and the introduction of a group C conjugate vaccine has reduced the incidence and carriage of the C serogroup significantly (3). Although these vaccines are working, they do not yet provide complete protection from meningococcal disease (4).The capsular polysaccharides of N. meningitidis are classified into 13 distinct serogroups based on their chemical structures (5). The capsules of serogroup B and C are homopolymers composed of α-2,8- or α-2,9-linked sialic acid, respectively, whereas serogroup Y and W-135 are heteropolymers of an α-2,6-linked sialic acid on glucose (Y) or galactose (W-135) (6, 7). N. meningitidis group B polysialic acid shares a biochemical epitope with the polysialylated form of the neural cell adhesion molecule of humans (8, 9). Because of this molecular mimicry of the polysialic acid-neural cell adhesion molecule, the bacterial capsular polysaccharide is thus considered a major virulence factor of N. meningitidis (5, 10).Serogroup C, Y, and W-135 of N. meningitidis modify their sialic acid capsules by O-acetylation of the sialic acid (11). Sialic acid is acetylated at the C-7 or C-8 position hydroxyl group in serogroup C, whereas the C-7 or C-9 position is acetylated in serogroup W-135 and Y (11). The O-acetylation of sialic acids is known to alter the physicochemical properties of the polysaccharide capsule (12). In addition, there is growing evidence that O-acetylation of the polysaccharide enhances bacterial pathogenesis by masking the protective epitope in the polysaccharide (13–16). For these reasons, considerable effort has been expended to identify and characterize sialic acid O-acetyltransferases in pathogenic bacteria.Recently, the sialic acid-specific O-acetyltransferases from group B Streptococcus, Campylobacter jejuni, Escherichia coli K1, and N. meningitidis serogroup C have been identified (17–20) with the latter two variants being the only ones to be characterized biochemically (21–23). These studies showed that bacterial sialic acid-specific O-acetyltransferases utilize an acetyl-CoA cofactor as a donor for the acetylation of their capsular sialic acid acceptor substrates (Fig. 1) and identified essential amino acid residues for potential catalytic roles in activity (22, 23). Although the gene encoding the capsule-specific O-acetyltransferase in N. meningitidis serogroup Y (known as OatWY) has been identified, biochemical characterization of the enzyme has not yet been reported. Furthermore, the lack of structural information on a sialic acid O-acetyltransferase from any bacterial species has hampered our ability to further understand the mode of substrate binding, specificity, and catalytic mechanism of this important sialic acid-modifying family.Open in a separate windowFIGURE 1.Reaction scheme of the OatWY-catalyzed O-acetyltransferase. Although acetylation of both the O-7 and O-9 hydroxyl group of the N. meningitidis serogroup Y polysialic acid has been implied through NMR analysis of the corresponding bacterial capsule (11), for simplicity only the O-9 transfer is shown here.Here we report the first kinetic and structural analysis of polysialic acid O-acetyltransferase OatWY from N. meningitidis serogroup Y in complex with either CoA, acetyl-CoA, or S-(2-oxopropyl)-CoA, which is a nonhydrolyzable acetyl-CoA substrate analog. Collectively, this study significantly contributes to our understanding of bacterial polysialic acid O-acetyltransferases, providing valuable insight into how capsular polysaccharide is acetylated in pathogenic bacteria.     

Polysialic Acid: Versatile Modification of NCAM, SynCAM 1 and Neuropilin-2

The glycan polysialic acid is well-known as a unique posttranslational modification of the neural cell adhesion molecule NCAM. Despite remarkable acceptor specificity, however, a few other proteins can be targets of polysialylation. Here, we recapitulate the biosynthesis of polysialic acid by the two polysialyltransferases ST8SIA2 and ST8SIA4 and highlight the increasing evidence that variation in the human ST8SIA2 gene is linked to schizophrenia and possibly other neuropsychiatric disorders. Moreover, we summarize the knowledge on the role of NCAM polysialylation in brain development gained by the analysis of NCAM- and polysialyltransferase-deficient mouse models. The last part of this review is focused on recent advances in identifying SynCAM 1 and neuropilin-2 as novel acceptors of polysialic acid in NG2 cells of the perinatal brain and in dendritic cells of the immune system, respectively.     

Polysialic acid production using Escherichia coli K1 in a disposable bag reactor

Polysialic acid (polySia), consisting of α‐(2,8)‐linked N‐acetylneuraminic acid monomers plays a crucial role in many biological processes. This study presents a novel process for the production of endogenous polySia using Escherichia coli K1 in a disposable bag reactor with wave‐induced mixing. Disposable bag reactors provide easy and fast production in terms of regulatory requirements as GMP, flexibility, and can easily be adjusted to larger production capacities not only by scale up but also by parallelization. Due to the poor oxygen transfer rate compared to a stirred tank reactor, pure oxygen was added during the cultivation to avoid oxygen limitation. During the exponential growth phase the growth rate was 0.61 h^?1. Investigation of stress‐related product release from the cell surface showed no significant differences between the disposable bag reactor with wave‐induced mixing and the stirred tank reactor. After batch cultivation a cell dry weight of 6.8 g L^?1 and a polySia concentration of 245 mg L^?1 were reached. The total protein concentration in the supernatant was 132 mg L^?1. After efficient and time‐saving downstream processing characterization of the final product showed a protein content of below 0.04 mg_protein/g_polySia and a maximal chain length of ～90 degree of polymerization.     

聚唾液酸,一种非GAGs、非免疫原性生物材料的应用研究进展

聚唾液酸是一种由N-乙酰神经氨酸连接、电负性的线性同聚物,存在于人体、动物细胞和少数致病菌中,主要以糖蛋白(神经细胞粘附分子)和糖脂形式存在,是一种非糖胺聚糖(GAGs)、非免疫原性、生物可降解的优良生物材料。聚唾液酸可用作组织工程和药物缓释材料,也可以与其它大分子复合形成功能材料。对聚唾液酸生物学功能、发酵生产及应用进行概述,以期为聚唾液酸的进一步应用研究提供参考。     

Polysialic acid controls NCAM-induced differentiation of neuronal precursors into calretinin-positive olfactory bulb interneurons

Understanding the mechanisms that regulate neurogenesis is a prerequisite for brain repair approaches based on neuronal precursor cells. One important regulator of postnatal neurogenesis is polysialic acid (polySia), a post-translational modification of the neural cell adhesion molecule NCAM. In the present study, we investigated the role of polySia in differentiation of neuronal precursors isolated from the subventricular zone of early postnatal mice. Removal of polySia promoted neurite induction and selectively enhanced maturation into a calretinin-positive phenotype. Expression of calbindin and Pax6, indicative for other lineages of olfactory bulb interneurons, were not affected. A decrease in the number of TUNEL-positive cells indicated that cell survival was slightly improved by removing polySia. Time lapse imaging revealed the absence of chain migration and low cell motility, in the presence and absence of polySia. The changes in survival and differentiation, therefore, could be dissected from the well-known function of polySia as a promoter of precursor migration. The differentiation response was mimicked by exposure of cells to soluble or substrate-bound NCAM and prevented by the C3d-peptide, a synthetic ligand blocking NCAM interactions. Moreover, a higher degree of differentiation was observed in cultures from polysialyltransferase-depleted mice and after NCAM exposure of precursors from NCAM-knockout mice demonstrating that the NCAM function is mediated via heterophilic binding partners. In conclusion, these data reveal that polySia controls instructive NCAM signals, which direct the differentiation of subventricular zone-derived precursors towards the calretinin-positive phenotype of olfactory bulb interneurons.