Biochemical engineering of cell surface sialic acids stimulates axonal growth.

Sialylation is essential for development and regeneration in mammals. Using N-propanoylmannosamine, a novel precursor of sialic acid, we were able to incorporate unnatural sialic acids with a prolonged N-acyl side chain (e.g., N-propanoylneuraminic acid) into cell surface glycoconjugates. Here we report that this biochemical engineering of sialic acid leads to a stimulation of neuronal cells. Both PC12 cells and cerebellar neurons showed a significant increase in neurite outgrowth after treatment with this novel sialic acid precursor. Furthermore, also the reestablishment of the perforant pathway was stimulated in brain slices. In addition, we surprisingly identified several cytosolic proteins with regulatory functions, which are differentially expressed after treatment with N-propanoylmannosamine. Because sialic acid is the only monosaccharide that is activated in the nucleus, we hypothesize that transcription could be modulated by the unnatural CMP-N-propanoylneuraminic acid and that sialic acid activation might be a general tool to regulate cellular functions, such as neurite outgrowth.