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Glycobiology Advance Access published online on March 24, 2004
Glycobiology, doi:10.1093/glycob/cwh069
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Submitted on January 9, 2004
Revised on February 26, 2004
Accepted on February 26, 2004

© 2004 Glycobiology © Oxford University Press 2004; all rights reserved.

ORIGINAL ARTICLES

N-glycan branching requirement in neuronal and post-natal viability

Zhengyi Ye 1 and Jamey D. Marth 1*

1 Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, Glycobiology Research and Training Center, 9500 Gilman Drive-0625, University of California San Diego, La Jolla, California 92093

* To whom correspondence should be addressed. E-mail: jmarth{at}ucsd.edu.

Abstract

The structural variations among extracellular N-glycans reflect the activity of glycosyltransferases and glycosidases that operate in the Golgi apparatus. More than other types of vertebrate glycans, N-glycans are typically highly branched oligosaccharides with multiple antennae linked to an underlying mannose core structure. The branching patterns of N-glycans consist of three types, termed high-mannose, hybrid, and complex. While most extracellular mammalian N-glycans are of the complex type, some cells variably express hybrid and high-mannose forms. Nevertheless, a requirement for hybrid and complex N-glycan branching exists in embryonic development and post-natal function among mice and humans inheriting defective Mgat1 or Mgat2 alleles. The resulting defects in formation N-glycan branching patterns cause multiple abnormalities including neurologic defects and have inferred the presence of distinct functions for hybrid and complex N-glycan branches among different cell lineages. We have further explored N-glycan structure-function relationships in vivo by using Cre-loxP conditional mutagenesis in order to abolish hybrid and complex N-glycan branching specifically among neuronal cells. Our findings show that hybrid N-glycan branching is an essential post-translational modification among neurons. Loss of Mgat1 resulted in a unique pattern of neuronal glycoprotein deficiency concurrent with caspase 3 activation and apoptosis. Such animals exhibited severe locomotor deficits, tremors, paralysis, and early post-natal death. Unexpectedly, neuronal Mgat2 deletion resulting in the loss of complex but not hybrid N-glycan branching was well tolerated without phenotypic markers of neuronal or locomotor dysfunction. Structural features associated with hybrid N-glycan branching comprise a requisite post-translational modification to neuronal glycoproteins that permits normal cellular function and viability.


N-Glycans, Neurobiology, Apoptosis, Genetics, Development
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