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Published 19 August 2002. doi:10.1083/jcb.200203125
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© The Rockefeller University Press, 0021-9525/2002/8/801 $5.00
The Journal of Cell Biology, Volume 158, Number 4, August 19, 2002 801-815

Article

 Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus

Peter L. Smith1,2, Jay T. Myers1, Clare E. Rogers1, Lan Zhou1,2, Bronia Petryniak1, Daniel J. Becker3, Jonathon W. Homeister1,2 and John B. Lowe1,2,3

1 Howard Hughes Medical Institute, The University of Michigan Medical School, Ann Arbor, MI 48109
2 Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI 48109
3 Graduate Program in Cellular and Molecular Biology, The University of Michigan Medical School, Ann Arbor, MI 48109

Address correspondence to John B. Lowe, Howard Hughes Medical Institute, MSRBI, Rm. 3510, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0650. Tel.: (734) 647-4779. Fax: (734) 936-1400. E-mail: JohnLowe{at}umich.edu

Glycoprotein fucosylation enables fringe-dependent modulation of signal transduction by Notch transmembrane receptors, contributes to selectin-dependent leukocyte trafficking, and is faulty in leukocyte adhesion deficiency (LAD) type II, also known as congenital disorder of glycosylation (CDG)-IIc, a rare human disorder characterized by psychomotor defects, developmental abnormalities, and leukocyte adhesion defects. We report here that mice with an induced null mutation in the FX locus, which encodes an enzyme in the de novo pathway for GDP–fucose synthesis, exhibit a virtually complete deficiency of cellular fucosylation, and variable frequency of intrauterine demise determined by parental FX genotype. Live-born FX(-/-) mice exhibit postnatal failure to thrive that is suppressed with a fucose-supplemented diet. FX(-/-) adults suffer from an extreme neutrophilia, myeloproliferation, and absence of leukocyte selectin ligand expression reminiscent of LAD-II/CDG-IIc. Contingent restoration of leukocyte and endothelial selectin ligand expression, general cellular fucosylation, and normal postnatal physiology is achieved by modulating dietary fucose to supply a salvage pathway for GDP–fucose synthesis. Conditional control of fucosylation in FX(-/-) mice identifies cellular fucosylation events as essential concomitants to fertility, early growth and development, and leukocyte adhesion.

Key Words: selectin; fucosylation; GDP–fucose; LAD-II; CDG-IIc


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