Polysialic Acid Profiles of Mice Expressing Variant Allelic Combinations of the Polysialyltransferases ST8SiaII and ST8SiaIV (2006)

The post-translational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) represents a remarkable example of dynamic modulation of homo- and heterophilic cell interactions by glycosylation. The synthesis of this unique carbohydrate polymer depends on the polysialyltransferases ST8SiaII and ST8SiaIV. Aiming to understand in more detail the contributions of ST8SiaII and ST8SiaIV to polySia biosynthesis in vivo, we used mutant mouse lines that differ in the number of functional polysialyltransferase alleles. The 1,2-diamino-4,5-methylenedioxybenzene method was used to qualitatively and quantitatively assess the polySia patterns. Similar to the wild-type genotype, long polySia chains (>50 residues) were detected in all genotypes expressing at least one functional polysialyltransferase allele. However, variant allelic combinations resulted in distinct alterations in the total amount of poly-Sia; the relative abundance of long, medium, and short polymers; and the ratio of polysialylated to non-polysialylated NCAM. In ST8SiaII-null mice, 45% of the brain NCAM was non-polysialylated, whereas a single functional allele of ST8SiaII was sufficient to polysialylate ∼90% of the NCAM pool. Our data reveal a complex polysialylation pattern and show that, under in vivo conditions, the coordinated action of ST8SiaII and ST8SiaIV is crucial to fine-tune the amount and structure of polySia on NCAM. The post-translational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) represents a remarkable example of dynamic modulation of homo- and heterophilic cell interactions by glycosylation. The synthesis of this unique carbohydrate polymer depends on the polysialyltransferases ST8SiaII and ST8SiaIV. Aiming to understand in more detail the contributions of ST8SiaII and ST8SiaIV to polySia biosynthesis in vivo, we used mutant mouse lines that differ in the number of functional polysialyltransferase alleles. The 1,2-diamino-4,5-methylenedioxybenzene method was used to qualitatively and quantitatively assess the polySia patterns. Similar to the wild-type genotype, long polySia chains (>50 residues) were detected in all genotypes expressing at least one functional polysialyltransferase allele. However, variant allelic combinations resulted in distinct alterations in the total amount of poly-Sia; the relative abundance of long, medium, and short polymers; and the ratio of polysialylated to non-polysialylated NCAM. In ST8SiaII-null mice, 45% of the brain NCAM was non-polysialylated, whereas a single functional allele of ST8SiaII was sufficient to polysialylate ∼90% of the NCAM pool. Our data reveal a complex polysialylation pattern and show that, under in vivo conditions, the coordinated action of ST8SiaII and ST8SiaIV is crucial to fine-tune the amount and structure of polySia on NCAM. Carbohydrate modifications of proteins and lipids play an important role in the development and maintenance of the nervous system as mediators of cell recognition events (1Kleene R. Schachner M. Nat. Rev. Neurosci. 2004; 5: 195-208Crossref PubMed Scopus (433) Google Scholar). One striking example is polysialic acid (polySia), 2The abbreviations used are: polySia, polysialic acid; NCAM, neural cell adhesion molecule; P1, postnatal day 1; mAb, monoclonal antibody; DMB, 1,2-diamino-4,5-methylenedioxybenzene; RT, reverse transcription; HPLC, high pressure liquid chromatography; DP, degree of polymerization. 2The abbreviations used are: polySia, polysialic acid; NCAM, neural cell adhesion molecule; P1, postnatal day 1; mAb, monoclonal antibody; DMB, 1,2-diamino-4,5-methylenedioxybenzene; RT, reverse transcription; HPLC, high pressure liquid chromatography; DP, degree of polymerization. a linear homopolymer of α2,8-linked N-acetylneuraminic acid. In vertebrates, polySia is found almost exclusively as a post-translational modification of the neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily. Attachment of polySia to NCAM was demonstrated to double the hydrodynamic radius of NCAM, thereby increasing the intermembrane space and disrupting the adhesive properties of NCAM and other cell adhesion molecules such as L1, integrins, and cadherins (2Fujimoto I. Bruses J.L. Rutishauser U. J. Biol. Chem. 2001; 276: 31745-31751Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 3Johnson C.P. Fujimoto I. Rutishauser U. Leckband D.E. J. Biol. Chem. 2005; 280: 137-145Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 4Yang P. Major D. Rutishauser U. J. Biol. Chem. 1994; 269: 23039-23044Abstract Full Text PDF PubMed Google Scholar). PolySia promotes migration of neuronal precursor cells, axonal outgrowth, and synaptic plasticity (for review, see Ref. 5Kiss J.Z. Rougon G. Curr. Opin. Neurobiol. 1997; 7: 640-646Crossref PubMed Scopus (207) Google Scholar). In addition to its function as a negative regulator of cell adhesion, polySia was shown to bind heparan sulfate proteoglycans (6Storms S.D. Rutishauser U. J. Biol. Chem. 1998; 273: 27124-27129Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), forming a complex that supports synaptogenesis and activity-dependent remodeling of synapses (7Dityatev A. Dityateva G. Sytnyk V. Delling M. Toni N. Nikonenko I. Muller D. Schachner M. J. Neurosci. 2004; 24: 9372-9382Crossref PubMed Scopus (221) Google Scholar). In addition, polySia can bind brain-derived neurotrophic factor to enhance brain-derived neurotrophic factor-dependent survival of cortical neurons (8Muller D. Djebbara-Hannas Z. Jourdain P. Vutskits L. Durbec P. Rougon G. Kiss J.Z. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4315-4320Crossref PubMed Scopus (196) Google Scholar, 9Vutskits L. Djebbara-Hannas Z. Zhang H. Paccaud J.P. Durbec P. Rougon G. Muller D. Kiss J.Z. Eur. J. Neurosci. 2001; 13: 1391-1402Crossref PubMed Google Scholar) and appears to be involved in the regulation of neurotransmitter receptor activity (10Vaithianathan T. Matthias K. Bahr B. Schachner M. Suppiramaniam V. Dityatev A. Steinhauser C. J. Biol. Chem. 2004; 279: 47975-47984Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). Whereas polySia levels are high during embryonic development, expression in the adult is restricted to brain areas of persistent neurogenesis and synaptic plasticity (11Seki T. Arai Y. Neurosci. Res. 1993; 17: 265-290Crossref PubMed Scopus (373) Google Scholar). Interestingly, the biosynthesis of polySia depends on two enzymes, the Golgi-resident polysialyltransferases ST8SiaII and ST8SiaIV, which share 59% identity at the amino acid sequence level. Each enzyme is independently capable of synthesizing polySia on NCAM, starting on complex N-glycans in the fifth Ig-like domain (12Kojima N. Tachida Y. Yoshida Y. Tsuji S. J. Biol. 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Glycobiology. 1998; PubMed Scopus Google Scholar, Res. 1997; PubMed Scopus Google Scholar, G. S. R. Res. 1997; PubMed Scopus Google Scholar). to distinct enzyme were in of ST8SiaII and ST8SiaIV. In the in ST8SiaII was found to ST8SiaIV K. M. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. S. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), and enzymes were to polySia chains with a degree of polysialylation K. M. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. M. J. Biol. Chem. 1998; 273: Full Text Full Text PDF Scopus Google Scholar). mouse ST8SiaII K. Dityatev A. A. Schachner M. M. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar) ST8SiaIV M. G. C. Schachner M. Gerardy-Schahn R. H. Dityatev A. J. Neurosci. 2000; PubMed Google Scholar) show of polySia and distinct by of polysialyltransferase B. R. I. M. S. Gerardy-Schahn R. H. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). The in the double is by postnatal in brain and the the can be by of NCAM, that polySia is a regulator of NCAM B. R. I. M. S. Gerardy-Schahn R. H. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). polysialyltransferase to the biosynthesis of this carbohydrate we ST8SiaII and ST8SiaIV to of all allelic a total of genotypes and double were at postnatal day and with to the NCAM polysialylation In this we reveal the in vivo of the complex NCAM polysialylation as by the coordinated of ST8SiaII and ST8SiaIV. and mouse monoclonal R. Eckhardt M. J. 1994; PubMed Scopus Google Scholar) and M. I. D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) were used on and was as K. A. M. Gerardy-Schahn R. R. Nat. Biol. 2005; PubMed Scopus Google Scholar). was acid and α2,8-linked acid of K. Dityatev A. A. Schachner M. M. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar) and ST8SiaIV M. G. C. Schachner M. Gerardy-Schahn R. H. Dityatev A. J. Neurosci. 2000; PubMed Google Scholar) were to The genotypes used in this were by single by and was as B. R. I. M. S. Gerardy-Schahn R. H. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). and mouse were B. R. I. M. S. Gerardy-Schahn R. H. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar), and one of was with on were by under conditions, of total were to and to and The of was on as the by mouse were with in of and were in a single and with in and was at by with and an were with negative brain were with in and at with and by was with of reverse was in a of of in of and of were at by at and was detected an system that one were and and ST8SiaIV, and were used and and all the were by the of a Res. 2001; PubMed Scopus Google Scholar). the and the amount of polySia, mouse were S. Y. 2001; PubMed Scopus Google Scholar, S. Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), and in a were in of and at with S. Y. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of the was by the addition of of to of of polySia we used an system with a and a at and and were used as at a of was by the and The was with S. Y. PubMed Scopus Google Scholar). of and of the were of areas and of the of PolySia the degree of polySia chains be NCAM. the method by and C. S. T. K. PubMed Scopus Google Scholar) and and S. Y. 2001; PubMed Scopus Google Scholar). this polySia chains are by acid and in with C. S. T. K. PubMed Scopus Google Scholar). the the that polySia to the of be of the S. Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). was in and D. J. Biol. 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Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), in polySia were in The in was to be wild-type mice, ST8SiaIV mice, and ST8SiaII In by the acid of to were detected polySia was a amount of was data show that ST8SiaII and ST8SiaIV are the enzymes synthesizing polySia with PolySia and in of ST8SiaII by the in the amount of polySia in was polySia in of wild-type and mutant mice, the total amount was by all areas of a starting with to with The are shown in Whereas of ST8SiaIV the total amount of polySia, ST8SiaII a to of the wild-type level. in the polySia amount to polymer the relative abundance of polymer was areas were and with wild-type which were to that of ST8SiaII to a in all polymer However, with increasing polymer the more and polySia with was to of the wild-type shown in ST8SiaIV a in the amount of long polySia of in ST8SiaII and ST8SiaIV allele on the polySia pattern in mouse amount of amount of polySia as by of polysialylated NCAM as by of the total amount of polySia to the of polysialylated with of polySia the as by amount of polySia as by of polysialylated NCAM as by of the total amount of polySia to the of polysialylated of polySia the as by in a In the areas to polySia chains of of the total areas in polySia in of the of the of the this we wild-type brain with increasing of double In this of the polySia to of long and all polymer to the of that the of the method is sufficient to alterations in the NCAM of and we the of polysialyltransferase on the NCAM expression and polysialylation to with all combinations of polysialyltransferase allele total of wild-type and double mice, were by and of brain were and used The are in α2,8-linked polySia with M. I. D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, J. S. P. M. J. PubMed Scopus Google Scholar), a polysialylated NCAM was in all genotypes double In with the of polySia demonstrated by the more was by with which polysialylated and non-polysialylated NCAM In wild-type the of a demonstrated that, at P1, all expressed NCAM was in the polysialylated non-polysialylated NCAM was detected in double as by two to and the NCAM at J. C. J. Biol. PubMed Scopus (115) Google Scholar). In and and the NCAM was almost with of the total NCAM in the non-polysialylated and In mice, 45% of the expressed NCAM was striking ST8SiaII ST8SiaIV was more in genotypes with one functional polysialyltransferase allele. Whereas in mice, of the brain NCAM was non-polysialylated, this to in and of polySia by of the brain with that, in all the NCAM pattern and levels were that polysialyltransferase NCAM the of NCAM expressed in the polysialylated was in with a ST8SiaII and of the NCAM were polysialylated in and mice, However, in the ratio the of polySia and polysialylated NCAM in the wild-type to to the that, in the amount of polySia to a single NCAM molecule is to the amount to NCAM in wild-type in mice, the of polysialylated NCAM to whereas the total polySia of the wild-type that polysialylated NCAM on polySia found in wild-type PolySia in of and the of polySia in is to of polySia in brain areas to a in polySia we the of polySia in of wild-type and ST8SiaII and ST8SiaIV of and brain were with and the are shown in In with data (11Seki T. Arai Y. Neurosci. Res. 1993; 17: 265-290Crossref PubMed Scopus (373) Google Scholar, A. D. Schachner M. J. PubMed Scopus Google Scholar), polySia was found almost in of wild-type and the with the and cortical were In the the was of whereas was in the and in the cortical and the the polySia expression and In the polySia expression pattern as in the wild-type brain was found and that the of polySia in is by a in polySia synthesis and is with of polySia in a of the of ST8SiaII and ST8SiaIV in of one polysialyltransferase is by an of the we the relative ST8SiaII and ST8SiaIV levels in brain of all genotypes by In the of was whereas of one allele of ST8SiaII ST8SiaIV resulted in a in the by in levels was found all of the of the polysialyltransferase of one allele was by of the of ST8SiaII more alterations in the polySia pattern ST8SiaIV we this is to in of levels of by is a that are with were all and to be to (for see by wild-type mouse a of ST8SiaII with ST8SiaIV S.D. in data on that levels of ST8SiaII with ST8SiaIV (16Hildebrandt H. Becker C. Murau M. Gerardy-Schahn R. Rahmann H. J. 1998; PubMed Scopus Google Scholar, N. Yoshida Y. N. Tsuji S. J. 1997; PubMed Scopus Google Scholar, J. K. L. T. Arai Y. M. Glycobiology. 1998; PubMed Scopus Google Scholar). of ST8SiaII and ST8SiaIV on the PolySia that ST8SiaII and ST8SiaIV levels with the number of functional the of in polysialyltransferase levels the polysialylation we to brain and expressing one functional polysialyltransferase allele. the of the genotypes be by the number of polysialyltransferase starting with the number of ST8SiaII with the wild-type of one ST8SiaII allele a in the amount of polySia chains with the alterations were in the of ST8SiaIV. the allele number of ST8SiaII to on the resulted in a in the total polySia to and alterations all polymer shown in and ST8SiaIV was by ST8SiaII alterations ST8SiaIV were on the ST8SiaII-null and Interestingly, the alterations were restricted to in the polySia and the as by of the two in PolySia in the single mice, in the total amount of polySia were by in brain of with one allele of a polysialyltransferase In and of the wild-type polySia were found In to the distinct in the the two single such was the genotypes as by in of the single and and and genotypes that the levels play an important role in the in the of of and demonstrated that genotypes total polySia levels total NCAM levels and patterns However, the two genotypes are in the of NCAM that is expressed in the polysialylated and in and in mice, the amount of polySia is to of the NCAM pool. The this is the of more polymer molecule in with two of ST8SiaIV with with one allele of ST8SiaII on of ST8SiaII and the of the we the of ST8SiaII and ST8SiaIV expression the of of double used in this shown in almost all expressed NCAM is polysialylated in this genotype, the pattern that of the wild-type and the patterns found in the two single that the ratio of ST8SiaII and ST8SiaIV is sufficient to the wild-type which depends on levels of genotypes are in which double and with one ST8SiaII allele In the genotype, a in the total amount of polySia was detected by abundance of all the addition of one allele of ST8SiaIV the total amount of polySia, the that, on more polySia molecule were However, the polymer the ST8SiaII double to to resulted in an in the polySia of in addition, to a in the by an in the abundance of polySia with that, with a single the pattern of all mutant that of wild-type Interestingly, in of the was a of long the amount of this was by polysialyltransferase PolySia an role during mouse development as by the of one polysialyltransferase K. Dityatev A. A. Schachner M. M. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. C. Schachner M. Gerardy-Schahn R. H. Dityatev A. J. Neurosci. 2000; PubMed Google Scholar) and by the postnatal of this unique carbohydrate polymer to of polysialyltransferase B. R. I. M. S. Gerardy-Schahn R. H. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). However, the of enzyme to the and of polySia in vivo a of mutant in the number of functional polysialyltransferase we demonstrated that alterations in the expression of ST8SiaII and ST8SiaIV the total amount of polySia, the the ratio of polysialylated to non-polysialylated NCAM, and the amount of polySia NCAM The of in of wild-type is in with the of polySia in embryonic and postnatal S. Y. PubMed Scopus Google Scholar). However, and D. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar) the of of polySia with of to in with ST8SiaIV of are to such long are restricted to polysialyltransferases more are the of polySia chains mouse demonstrated that, in vivo, enzyme is to polySia with in to in data that ST8SiaII ST8SiaIV K. M. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. S. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). In enzymes a degree of polysialylation enzyme K. M. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. M. J. Biol. Chem. 1998; 273: Full Text Full Text PDF Scopus Google Scholar). was in vivo in mice, enzymes and the total polySia was the of polySia found in the two single in ST8SiaII to be in polySia synthesis with ST8SiaIV (12Kojima N. Tachida Y. Yoshida Y. Tsuji S. J. Biol. Chem. 1996; 271: 19457-19463Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, K. M. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. S. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. J. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), the striking in NCAM polysialylation in vivo were found to be to ST8SiaII of ST8SiaIV the total polySia whereas of ST8SiaII resulted in a by by an and an in non-polysialylated NCAM to of in and in vivo that enzyme on the all in were with enzymes the domain NCAM is to the during its to the cell of enzyme and in and other properties of the In with the overlapping expression patterns of ST8SiaII and ST8SiaIV found in and at embryonic day J. K. L. T. Arai Y. M. Glycobiology. 1998; PubMed Scopus Google Scholar, Res. 1997; PubMed Scopus Google Scholar), the of one polysialyltransferase the expression pattern of polySia in of the of non-polysialylated NCAM of the total found in brain be to the of ST8SiaII in a brain In mice, the amount of NCAM was to whereas in the of a single allele of ST8SiaII of the brain NCAM was of remarkable in the of the two enzymes to the NCAM can be to enzyme levels a of ST8SiaII in the (16Hildebrandt H. Becker C. Murau M. Gerardy-Schahn R. Rahmann H. J. 1998; PubMed Scopus Google Scholar, N. Yoshida Y. N. Tsuji S. J. 1997; PubMed Scopus Google Scholar, J. K. L. T. Arai Y. M. Glycobiology. 1998; PubMed Scopus Google Scholar). However, as by J. K. L. T. Arai Y. M. Glycobiology. 1998; PubMed Scopus Google Scholar), ST8SiaII levels by in be with a which we that, in wild-type the ST8SiaII was the ST8SiaIV level. the demonstrated that, in the of a single ST8SiaII allele more NCAM was polysialylated in the of two ST8SiaIV total polysialyltransferase levels were found in that the NCAM polysialylation of ST8SiaII and ST8SiaIV are to properties of the two In with in vivo data a NCAM polysialylation in shown a NCAM ST8SiaII with ST8SiaIV S. S. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The that the polySia levels in single to of the wild-type that polysialyltransferase can to a the of the other and show that ST8SiaII is more in the of ST8SiaIV The supports in data that ST8SiaIV more on NCAM that polysialic acid on one of the and that ST8SiaIV can acid by ST8SiaII K. M. M. J. Biol. Chem. 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A. Schachner M. M. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), that during the postnatal Interestingly, the are the polysialylation by ST8SiaIV of the In with the that ST8SiaII is by ST8SiaIV, of brain alterations of NCAM polysialylation in ST8SiaII-null of polySia by an and 45% of the NCAM to the non-polysialylated ST8SiaIV is almost by ST8SiaII in the polySia and the NCAM in the polysialylated in adult mice, in which ST8SiaII and ST8SiaIV expression of ST8SiaIV a that is with synaptic plasticity in the of the M. G. C. Schachner M. Gerardy-Schahn R. H. Dityatev A. J. Neurosci. 2000; PubMed Google Scholar). In this is of polySia M. G. C. Schachner M. Gerardy-Schahn R. H. Dityatev A. J. 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