Abstract
All vertebrate cell surfaces display a dense glycan layer often terminated with sialic acids, which have multiple functions due to their location and diverse modifications. The major sialic acids in most mammalian tissues are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), the latter being derived from Neu5Ac via addition of one oxygen atom at the sugar nucleotide level by CMP-Neu5Ac hydroxylase (Cmah). Contrasting with other organs that express various ratios of Neu5Ac and Neu5Gc depending on the variable expression of Cmah, Neu5Gc expression in the brain is extremely low in all vertebrates studied to date, suggesting that neural expression is detrimental to animals. However, physiological exploration of the reasons for this long term evolutionary selection has been lacking. To explore the consequences of forced expression of Neu5Gc in the brain, we have established brain-specific Cmah transgenic mice. Such Neu5Gc overexpression in the brain resulted in abnormal locomotor activity, impaired object recognition memory, and abnormal axon myelination. Brain-specific Cmah transgenic mice were also lethally sensitive to a Neu5Gc-preferring bacterial toxin, even though Neu5Gc was overexpressed only in the brain and other organs maintained endogenous Neu5Gc expression, as in wild-type mice. Therefore, the unusually strict evolutionary suppression of Neu5Gc expression in the vertebrate brain may be explained by evasion of negative effects on neural functions and by selection against pathogens.
Highlights
All vertebrate cell surfaces display a dense glycan layer often terminated with sialic acids, which have multiple functions due to their location and diverse modifications
The major sialic acids in most mammalian tissues are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), the latter being derived from Neu5Ac via addition of one oxygen atom at the sugar nucleotide level by CMP-Neu5Ac hydroxylase (Cmah)
Contrasting with other organs that express various ratios of Neu5Ac and Neu5Gc depending on the variable expression of Cmah, Neu5Gc expression in the brain is extremely low in all vertebrates studied to date, suggesting that neural expression is detrimental to animals
Summary
Trace Amounts of Neu5Gc Reported in Vertebrate Brains Are Primarily in Endothelial Cells—Biochemical analyses found very low amounts of Neu5Gc (Ͻ3%) in all vertebrate brains tested to date even in species that express high levels of Neu5Gc in other tissues [30]. Lethality Observed in Initial Attempts to Overexpress Cmah in the Developing Embryo—To explore the evolutionary advantage of this specific and extreme suppression of Neu5Gc in vertebrate brain for hundreds of millions of years of evolution, we first tried to make mice with increased Neu5Gc in the brain by forced expression of the Cmah cDNA encoding the enzyme responsible for Neu5Gc biosynthesis. Cytomegalovirus (CMV) promoter or neuron-specific enolase (NSE) promoter was used to express transgene-derived Cmah in a systemic or neuron-specific manner, respectively [33]. In both instances, no live mice with Neu5Gc expression in the brain were obtained (Table 1). Results of initial attempts to produce transgenic mice with brain expression of Neu5Gc Cmah cDNA was expressed under CMV promoter or NSE promoter. The numbers of live births and transgene-positive mice were indicated
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
