Expression and regulation of sialic acid biosynthesis and sialyltransferase genes in the mammary gland
thesisposted on 18.05.2017 by Maksimovic, Jovana
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Sialic acids are a family of nine-carbon, acidic monosaccharides. In mammals, they are typically located at the non-reducing terminus of oligosaccharide chains, connected either via an α2,3- or α2,6- linkage. Sialic acids can also form α2,8-linked poly-sialic acid chains on gangliosides and glycoproteins. Milk sialylglycoconjugates can protect the gastrointestinal tract of the suckling neonate by competitively binding to invading pathogens and promoting growth of beneficial flora, and their potential role in post-natal brain development is of particular interest in human infant nutrition. Although the concentration and distribution of sialylglycoconjugates has been extensively studied in the milk of various species, the regulation of sialylation in the mammary gland, in the context of lactation, has been limited. Sialic acid can be synthesised in all tissues to satisfy local sialylation requirements, although the final complement of sialylated structures is determined by the sialyltransferase enzymes. Sialyltransferases are a family of Golgi membrane-bound, glycosyltransferases that transfer sialic acid from CMP-sialic acid to carbohydrate acceptor groups of glycoproteins, glycolipids and free oligosaccharides, forming various sialylglycoconjugates. Their expression is primarily controlled at the level of transcription and is expedited through the use of several tissue and development-specific promoters, giving rise to numerous transcripts divergent only in their 5’ untranslated regions. Thus far, 20 mammalian sialyltransferases have been cloned. Depending on the type of linkage formed and the type of sugar acceptor, they are segregated into four groups: ST6Gal, ST6GalNAc, ST3Gal and ST8Sia. This study describes the expression of sialic acid biosynthesis and sialyltransferase genes in the lactating eutherian and marsupial mammary gland and the role of lactogenic hormones in their regulation. It also examines the developmental context in which milk iv sialylglycoconjugates may be important. Analysis of mouse mammary gland lactation microarray time course data revealed that key sialic acid biosynthesis genes are upregulated during lactation, but that only a subset of known sialyltransferase genes are expressed at all. Explant culture of mouse mammary tissue demonstrated that lactogenic hormones are involved in the regulation of the genes found to be differentially expressed during mouse lactation. These genes were subsequently characterised in the tammar wallaby and their expression assayed across the lactation cycle. A correlation was observed between the developmental state of the tammar neonate at peak mammary gland sialyltransferase gene expression and the developmental state of the mouse at birth, suggesting that an increase in sialylated milk products is particularly important during this developmental stage. Analysis of the expression of the ST6Gal I gene in the bovine mammary gland during lactation, showed a remarkably different profile of expression to that of the mouse and wallaby. In conclusion, this study has demonstrated that transcriptional control is a key factor in the regulation of sialylation in the mammary gland during lactation and that lactogenic hormones drive the changes in gene expression. Also, given the difference in ST6Gal I gene expression between mice and cows, it is apparent that the regulation of sialylation varies between different species, possibly catering for the developmental state of the young at birth.