Abstract
ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 (ST8SIA2) synthesizes polysialic acid (PSA), which is essential for brain development. Although previous studies reported that St8sia2-deficient mice that have a mixed 129 and C57BL/6 (B6) genetic background showed mild and variable phenotypes, the reasons for this remain unknown. We hypothesized that this phenotypic difference is caused by diversity in the expression or function of flanking genes of St8sia2. A genomic polymorphism and gene expression analysis in the flanking region revealed reduced expression of insulin-like growth factor 1 receptor (Igf1r) on the B6 background than on that of the 129 strain. This observation, along with the finding that administration of an IGF1R agonist during pregnancy increased litter size, suggests that the decreased expression of Igf1r associated with ST8SIA2 deficiency caused lethality. This study demonstrates the importance of gene expression level in the flanking regions of a targeted null allele having an effect on phenotype.
Highlights
Glycosylation is one of the important post-translational modifications of proteins
Lithium therapy rescues hydrocephalus by inhibition of glycogen synthase kinase 3-β (GSK3β) activity[24]
We observed that St8sia[2] homozygous mutants increased incidence of hydrocephalus and embryonic lethality after their genetic background was purified by additional backcrosses to backcrossed to the C57BL/6 (B6) up to almost inbred mice level (Figs 1 and 2)
Summary
Glycosylation is one of the important post-translational modifications of proteins. ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 (ST8SIA2) is one of the enzymes that synthesize polysialic acid (PSA), which is crucial for brain development[1,2,3,4]. One previous report found that St8sia2−/− mouse strains are normal[11], but a more recent one demonstrated that the mutant mice have mild hydrocephalus[12] The origin of this phenotypic difference has not been delineated. 129 and B6 strains have many differences between their gene expression profiles, both in the bodies and brains of adults and neonates[17,18]. This phenotypic variation due to flanking gene effects has been reported most often for behavioural phenotypes[19,20,21]. We found that the variability in gene expression in the flanking regions of the St8sia[2] locus contributed significantly to these phenotypic differences. By identifying polymorphisms allowing us to map flanking regions, it may allow the explanation of variable mutant phenotypes observed with targeting of a single gene
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