The directed migration of gonadal distal tip cells in Caenorhabditis elegans requires NGAT-1, a ß1,4-N-acetylgalactosaminyltransferase enzyme
| Autor: | James W. Dennis, Lijia W. Zhang, Joseph G. Culotti, Wendy L. Johnston, Alexa Bennett, Joseph Veyhl, Harry Schachter, Robert J. Dunn |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Nematoda Mutant Glycobiology lcsh:Medicine Biochemistry Cell Movement Nucleic Acids Medicine and Health Sciences lcsh:Science Caenorhabditis elegans chemistry.chemical_classification Neurons Multidisciplinary biology Animal Behavior Cell migration Animal Models Null allele Phenotype Phenotypes Experimental Organism Systems N-Acetylgalactosaminyltransferases Anatomy Genital Anatomy Research Article Animal Navigation Glycan N-Acetylglucosaminyltransferases Research and Analysis Methods 03 medical and health sciences Model Organisms Genetics Animals Caenorhabditis elegans Proteins Gonads Molecular Biology Techniques Gene Molecular Biology Glycoproteins Behavior lcsh:R Reproductive System Organisms Biology and Life Sciences DNA biology.organism_classification Molecular biology Invertebrates 030104 developmental biology chemistry Mutation biology.protein Caenorhabditis lcsh:Q Animal Migration Glycoprotein Zoology Cloning |
| Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 8, p e0183049 (2017) |
| ISSN: | 1932-6203 |
| Popis: | Glycoproteins such as growth factor receptors and extracellular matrix have well-known functions in development and cancer progression, however, the glycans at sites of modification are often heterogeneous molecular populations which makes their functional characterization challenging. Here we provide evidence for a specific, discrete, well-defined glycan modification and regulation of a stage-specific cell migration in Caenorhabditis elegans. We show that a chain-terminating, putative null mutation in the gene encoding a predicted β1,4-N-acetylgalactosaminyltransferase, named ngat-1, causes a maternally rescued temperature sensitive (ts) defect in the second phase of the three phase migration pattern of the posterior, but not the anterior, hermaphrodite Distal Tip Cell (DTC). An amino-terminal partial deletion of ngat-1 causes a similar but lower penetrance ts phenotype. The existence of multiple ts alleles with distinctly different molecular DNA lesions, neither of which is likely to encode a ts protein, indicates that NGAT-1 normally prevents innate temperature sensitivity for phase 2 DTC pathfinding. Temperature shift analyses indicate that the ts period for the ngat-1 mutant defect ends by the beginning of post-embryonic development-nearly 3 full larval stages prior to the defective phase 2 migration affected by ngat-1 mutations. NGAT-1 homologs generate glycan-terminal GalNAc-β1-4GlcNAc, referred to as LacdiNAc modifications, on glycoproteins and glycolipids. We also found that the absence of the GnT1/Mgat1 activity [UDP-N-acetyl-D-glucosamine:α-3-D-mannoside β-1,2-N-acetylglucosaminyltransferase 1 (encoded by C. elegans gly-12, gly-13, and gly-14 and homologous to vertebrate GnT1/Mgat1)], causes a similar spectrum of DTC phenotypes as ngat-1 mutations-primarily affecting posterior DTC phase 2 migration and preventing manifestation of the same innate ts period as ngat-1. GnT1/Mgat1 is a medial Golgi enzyme known to modify mannose residues and initiate N-glycan branching, an essential step in the biosynthesis of hybrid, paucimannose and complex-type N-glycans. Quadruple mutant animals bearing putative null mutations in ngat-1 and the three GnT genes (gly-12, gly-13, gly-14) were not enhanced for DTC migration defects, suggesting NGAT-1 and GnT1 act in the same pathway. These findings suggest that GnTI generates an N-glycan substrate for NGAT-1 modification, which is required at restrictive temperature (25°C) to prevent, stabilize, reverse or compensate a perinatal thermo-labile process (or structure) causing late larval stage DTC phase 2 migration errors. |
| Databáze: | OpenAIRE |
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