N-glycan branching requirement in neuronal and postnatal viability.
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 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. Though 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 postnatal 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 to abolish hybrid and complex N-glycan branching specifically among neuronal cells. Our findings show that hybrid N-glycan branching is an essential posttranslational 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 postnatal 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 posttranslational modification to neuronal glycoproteins that permits normal cellular function and viability.
Ye
Zhengyi
Z
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, CA 92093, USA.
Marth
Jamey D
JD
D000217:Acyltransferases / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D017353:Gene Deletion; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D051379:Mice; D016296:Mutagenesis; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism
D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D011134:Polysaccharides; D000217:Acyltransferases; C459903:MGAT1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; C063313:alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase