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Molecular and Cellular Biology, February 2004, p. 1680-1690, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1680-1690.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Ogt-Dependent X-Chromosome-Linked Protein Glycosylation Is a Requisite Modification in Somatic Cell Function and Embryo Viability

Niall O'Donnell,1,{dagger} Natasha E. Zachara,2 Gerald W. Hart,2 and Jamey D. Marth1*

Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California San Diego, La Jolla, California 92093-0625,1 Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-21852

Received 4 August 2003/ Returned for modification 11 November 2003/ Accepted 21 November 2003

The Ogt gene encodes a glycosyltransferase that links N-acetylglucosamine to serine and threonine residues (O-GlcNAc) on nuclear and cytosolic proteins. Efforts to study a mammalian model of Ogt deficiency have been hindered by the requirement for this X-linked gene in embryonic stem cell viability, necessitating the use of conditional mutagenesis in vivo. We have extended these observations by segregating Ogt mutation to distinct somatic cell types, including neurons, thymocytes, and fibroblasts, the latter by an approach developed for inducible Ogt mutagenesis. We show that Ogt mutation results in the loss of O-GlcNAc and causes T-cell apoptosis, neuronal tau hyperphosphorylation, and fibroblast growth arrest with altered expression of c-Fos, c-Jun, c-Myc, Sp1, and p27. We further segregated the mutant Ogt allele to parental gametes by oocyte- and spermatid-specific Cre-loxP mutagenesis. By this we established an in vivo genetic approach that supports the ontogeny of female heterozygotes bearing mutant X-linked genes required during embryogenesis. Successful production and characterization of such female heterozygotes further indicates that mammalian cells commonly require a functional Ogt allele. We find that O-GlcNAc modulates protein phosphorylation and expression among essential and conserved cell signaling pathways.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, 9500 Gilman Dr., 0625, CMM-W Bldg. Rm. 333, University of California San Diego, La Jolla, CA 92093. Phone: (858) 534-6526. Fax: (858) 534-6724. E-mail: jmarth{at}ucsd.edu.

{dagger} Present address: Johnson and Johnson, Pharmaceutical Research and Development, San Diego, CA 92121.

Molecular and Cellular Biology, February 2004, p. 1680-1690, Vol. 24, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.4.1680-1690.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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