Impact of the polysialyltransferases ST8SiaII and ST8SiaIV on polysialic acid synthesis during postnatal mouse brain development.
Polysialic acid (polySia), a post-translational modification of the neural cell adhesion molecule (NCAM), is the key regulator of NCAM-mediated functions and crucial for normal brain development, postnatal growth, and survival. Two polysialyltransferases, ST8SiaII and ST8SiaIV, mediate polySia biosynthesis. To dissect the impact of each enzyme during postnatal brain development, we monitored the developmental changes in NCAM polysialylation in wild-type, ST8SiaII-, and ST8SiaIV-deficient mice using whole brain lysates obtained at 10 time points from postnatal days 1 to 21 and from adult mice. In wild-type and ST8SiaIV-null brain, polySia biosynthesis kept pace with the rapid increase in brain weight until day 9, and nearly all NCAM was polysialylated. Thereafter, polySia dropped by approximately 70% within 1 week, accompanied by the first occurrence of polySia-free NCAM-140 and NCAM-180. In ST8SiaII-null brain, polySia declined immediately after birth, leading to 60% less polySia at day 9 combined with the untimely appearance of polySia-free NCAM. Polysialyltransferase deficiency did not alter NCAM expression level or isoform pattern. In all three genotypes, NCAM-140 and NCAM-180 were expressed at constant levels from days 1 to 21 and provided the major polySia acceptors. By contrast, NCAM-120 first appeared at day 5, followed by a strong up-regulation inverse to the decrease in polySia. Together, we provide a comprehensive quantitative analysis of the developmental changes in polySia level, NCAM polysialylation status, and polysialyltransferase transcript levels and show that the predominant role of ST8SiaII during postnatal brain development is restricted to the first 15 days.
Oltmann-Norden
Imke
I
Institute of Cellular Chemistry, Medical School Hannover, D-30625 Hannover, Germany.
Galuska
Sebastian P
SP
Institute of Biochemistry, Medical Faculty, University of Giessen, D-35392 Giessen, Germany.
Hildebrandt
Herbert
H
Institute of Cellular Chemistry, Medical School Hannover, D-30625 Hannover, Germany.
Geyer
Rudolf
R
Institute of Biochemistry, Medical Faculty, University of Giessen, D-35392 Giessen, Germany.
Gerardy-Schahn
Rita
R
Institute of Cellular Chemistry, Medical School Hannover, D-30625 Hannover, Germany.
Geyer
Hildegard
H
Institute of Biochemistry, Medical Faculty, University of Giessen, D-35392 Giessen, Germany.
Mühlenhoff
Martina
M
Institute of Cellular Chemistry, Medical School Hannover, D-30625 Hannover, Germany. Electronic address: muehlenhoff.martina@mh-hannover.de.
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000033:anatomy & histology / Q000196:embryology* / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012794:Sialic Acids / Q000096:biosynthesis*; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*
D019006:Neural Cell Adhesion Molecules; D020033:Protein Isoforms; D012333:RNA, Messenger; D012794:Sialic Acids; C021319:polysialic acid; C526452:ST8SiaII protein, mouse; D012799:Sialyltransferases; C525848:ST8SiaIV protein, mouse