Truncated, inactive N-acetylglucosaminyltransferase III (GlcNAc-TIII) induces neurological and other traits absent in mice that lack GlcNAc-TIII

Riddhi Bhattacharyya, Mantu Bhaumik, T. Shantha Raju, Pamela Stanley

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

N-Acetylglucosaminyltransferase III (GlcNAc-TIII), the product of the Mgat3 gene, transfers the bisecting GlcNAc to the core mannose of complex N-glycans. The addition of this residue is regulated during development and has functional consequences for receptor signaling, cell adhesion, and tumor progression. Mice homozygous for a null mutation at the Mgat3 locus (Mgat3Δ) or for a targeted mutation in the Mgat3 gene (previously called Mgat3neo, but herein renamed Mgat3T37 because the allele generates inactive GlcNAc-TIII of ∼37 kDa) were found to exhibit retarded progression of liver tumors. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of neutral N-glycans from kidneys revealed no significant differences, and both mutants showed the expected lack of N-glycan species with an additional GlcNAc. However, the two mutants differed in several biological traits. Mgat3T37/T37 homozygotes in a mixed or 129SvJ background were retarded in growth rate and exhibited an altered leg clasp reflex, an altered gait, and defective nursing behavior. Pups abandoned by Mgat3T37/T37 mothers were rescued by wild-type foster mothers. None of these Mgat3T37/T37 traits were exhibited by Mgat3Δ/Δ mice or by heterozygous mice carrying the Mgat3T37 mutation. Similarly, no dominant-negative effect was observed in Chinese hamster ovary cells expressing truncated GlcNAc-TIII in the presence of wild-type GlcNAc-TIII. However, compound heterozygotes carrying both the Mgat3T37 and Mgat3Δ mutations exhibited a marked leg clasp reflex, indicating that in the absence of wild-type GlcNAc-TIII, truncated GlcNAc-TIII causes this phenotype. The Mgat3 gene was expressed in brain at embryonic day 10.5 and thereafter and in neurons of adult cerebellum. The mutant Mgat3 gene was also highly expressed in Mgat3T37/T37 brain. This may be the basis of the unexpected neurological phenotype induced by truncated, inactive GlcNAc-TIII in the mouse.

Original languageEnglish (US)
Pages (from-to)26300-26309
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number29
DOIs
StatePublished - Jul 19 2002

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beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase
Polysaccharides
Genes
Mutation
Tumors
Brain
Gene transfer
Reflex
Leg
Nursing
Cell adhesion
Mannose
Phenotype
Liver
Neurons
Ionization
Mass spectrometry
Desorption
Homozygote
Heterozygote

ASJC Scopus subject areas

  • Biochemistry

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Truncated, inactive N-acetylglucosaminyltransferase III (GlcNAc-TIII) induces neurological and other traits absent in mice that lack GlcNAc-TIII. / Bhattacharyya, Riddhi; Bhaumik, Mantu; Shantha Raju, T.; Stanley, Pamela.

In: Journal of Biological Chemistry, Vol. 277, No. 29, 19.07.2002, p. 26300-26309.

Research output: Contribution to journalArticle

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abstract = "N-Acetylglucosaminyltransferase III (GlcNAc-TIII), the product of the Mgat3 gene, transfers the bisecting GlcNAc to the core mannose of complex N-glycans. The addition of this residue is regulated during development and has functional consequences for receptor signaling, cell adhesion, and tumor progression. Mice homozygous for a null mutation at the Mgat3 locus (Mgat3Δ) or for a targeted mutation in the Mgat3 gene (previously called Mgat3neo, but herein renamed Mgat3T37 because the allele generates inactive GlcNAc-TIII of ∼37 kDa) were found to exhibit retarded progression of liver tumors. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of neutral N-glycans from kidneys revealed no significant differences, and both mutants showed the expected lack of N-glycan species with an additional GlcNAc. However, the two mutants differed in several biological traits. Mgat3T37/T37 homozygotes in a mixed or 129SvJ background were retarded in growth rate and exhibited an altered leg clasp reflex, an altered gait, and defective nursing behavior. Pups abandoned by Mgat3T37/T37 mothers were rescued by wild-type foster mothers. None of these Mgat3T37/T37 traits were exhibited by Mgat3Δ/Δ mice or by heterozygous mice carrying the Mgat3T37 mutation. Similarly, no dominant-negative effect was observed in Chinese hamster ovary cells expressing truncated GlcNAc-TIII in the presence of wild-type GlcNAc-TIII. However, compound heterozygotes carrying both the Mgat3T37 and Mgat3Δ mutations exhibited a marked leg clasp reflex, indicating that in the absence of wild-type GlcNAc-TIII, truncated GlcNAc-TIII causes this phenotype. The Mgat3 gene was expressed in brain at embryonic day 10.5 and thereafter and in neurons of adult cerebellum. The mutant Mgat3 gene was also highly expressed in Mgat3T37/T37 brain. This may be the basis of the unexpected neurological phenotype induced by truncated, inactive GlcNAc-TIII in the mouse.",
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T1 - Truncated, inactive N-acetylglucosaminyltransferase III (GlcNAc-TIII) induces neurological and other traits absent in mice that lack GlcNAc-TIII

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AU - Shantha Raju, T.

AU - Stanley, Pamela

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AB - N-Acetylglucosaminyltransferase III (GlcNAc-TIII), the product of the Mgat3 gene, transfers the bisecting GlcNAc to the core mannose of complex N-glycans. The addition of this residue is regulated during development and has functional consequences for receptor signaling, cell adhesion, and tumor progression. Mice homozygous for a null mutation at the Mgat3 locus (Mgat3Δ) or for a targeted mutation in the Mgat3 gene (previously called Mgat3neo, but herein renamed Mgat3T37 because the allele generates inactive GlcNAc-TIII of ∼37 kDa) were found to exhibit retarded progression of liver tumors. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of neutral N-glycans from kidneys revealed no significant differences, and both mutants showed the expected lack of N-glycan species with an additional GlcNAc. However, the two mutants differed in several biological traits. Mgat3T37/T37 homozygotes in a mixed or 129SvJ background were retarded in growth rate and exhibited an altered leg clasp reflex, an altered gait, and defective nursing behavior. Pups abandoned by Mgat3T37/T37 mothers were rescued by wild-type foster mothers. None of these Mgat3T37/T37 traits were exhibited by Mgat3Δ/Δ mice or by heterozygous mice carrying the Mgat3T37 mutation. Similarly, no dominant-negative effect was observed in Chinese hamster ovary cells expressing truncated GlcNAc-TIII in the presence of wild-type GlcNAc-TIII. However, compound heterozygotes carrying both the Mgat3T37 and Mgat3Δ mutations exhibited a marked leg clasp reflex, indicating that in the absence of wild-type GlcNAc-TIII, truncated GlcNAc-TIII causes this phenotype. The Mgat3 gene was expressed in brain at embryonic day 10.5 and thereafter and in neurons of adult cerebellum. The mutant Mgat3 gene was also highly expressed in Mgat3T37/T37 brain. This may be the basis of the unexpected neurological phenotype induced by truncated, inactive GlcNAc-TIII in the mouse.

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