Abstract
Polysialic acid (PSA) is a unique carbohydrate composed of a linear homopolymer of α-2,8 linked sialic acid, and is mainly attached to the fifth immunoglobulin-like domain of the neural cell adhesion molecule (NCAM) in vertebrate neural system. In the brain, PSA is exclusively synthesized by the two polysialyltransferases ST8SiaII (also known as STX) and ST8SiaIV (also known as PST). By modulating adhesive property of NCAM, PSA plays a critical role in several neural development processes such as cell migration, neurite outgrowth, axon pathfinding, synaptogenesis and activity-dependent plasticity. The expression of PSA is temporally and spatially regulated during neural development and a tight regulation of PSA expression is essential to its biological function. In mouse visual cortex, PSA is downregulated following eye opening and its decrease allows the maturation of GABAergic synapses and the opening of the critical period for ocular dominance plasticity. Relatively little is known about how PSA levels are regulated by sensory experience and neuronal activity. Here, we demonstrate that while both ST8SiaII and ST8SiaIV mRNA levels decrease around the time of eye opening in mouse visual cortex, only ST8SiaII mRNA level reduction is regulated by sensory experience. Using an organotypic culture system from mouse visual cortex, we further show that ST8SiaII gene expression is regulated by spiking activity and NMDA-mediated excitation. Further, we show that both ST8SiaII and ST8SiaIV mRNA levels are positively regulated by PKC-mediated signaling. Therefore, sensory experience-dependent ST8SiaII gene expression regulates PSA levels in postnatal visual cortex, thus acting as molecular link between visual activity and PSA expression.
Highlights
Polysialic acid (PSA) moiety is a long, linear homopolymer of a2,8-linked sialic acid attached almost exclusively to the neural cell adhesion molecule (NCAM) in vertebrates [1]
To correct for inter-individual variability in gene expression, we normalized the mRNA levels measured in occipital, visual cortex (OC) by those measured in parietal cortex (PC), as described in Di Cristo et al (2007) [8]
We further confirmed that PSA expression, quantified by immunoblot analysis, remained significantly higher in visual cortex from BD mice compared to P25 control littermates (Figure 2C, n = 3 P25 Ctr mice, n = 3 P25 BD mice; Mann-Whitney test, p,0.001), to what occurs in mice dark-reared from birth [8]
Summary
Polysialic acid (PSA) moiety is a long, linear homopolymer of a2,8-linked sialic acid attached almost exclusively to the neural cell adhesion molecule (NCAM) in vertebrates [1]. PSA modulates cell adhesion and signal transduction events mediated by NCAM and other adhesion molecules by virtue of its polyanionic nature and large hydrated volume [2]. Its expression may represent a regulated permissive signal for allowing optimal levels of interactions between cell-cell or cell-extracellular matrix, which may either promote or inhibit specific morphogenic events at the appropriate time and with the appropriate order. In this context, a tight regulation of PSA expression appears to be essential to its biological function. A key issue is how the expression of PSA is regulated as a part of physiological process in the brain
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