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J. Biol. Chem., Vol. 282, Issue 4, 2558-2566, January 26, 2007

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Respiratory Distress and Neonatal Lethality in Mice Lacking Golgi 1,2-Mannosidase IB Involved in N-Glycan Maturation^*

Linda O. Tremblay, Erzsebet Nagy Kovács, Eugene Daniels, Nyet Kui Wong^¶, Mark Sutton-Smith^¶, Howard R. Morris^¶, Anne Dell^¶, Edwige Marcinkiewicz^||, Nabil G. Seidah^||, Colin McKerlie^**, and Annette Herscovics¹

From the McGill Cancer Centre and the Department of Anatomy and Cell Biology, McGill University, Montréal, Québec H3G 1Y6, Canada, the ^¶Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, United Kingdom, the ^||Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montréal, Montréal, Québec H2W 1R7, Canada, and the ^**Program in Lung Biology Research, The Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada

There are three mammalian Golgi 1,2-mannosidases, encoded by different genes, that form Man₅GlcNAc₂ from Man_8-9GlcNAc₂ for the biosynthesis of hybrid and complex N-glycans. Northern blot analysis and in situ hybridization indicate that the three paralogs display distinct developmental and tissue-specific expression. The physiological role of Golgi 1,2-mannosidase IB was investigated by targeted gene ablation. The null mice have normal gross appearance at birth, but they display respiratory distress and die within a few hours. Histology of fetal lungs the day before birth indicate some delay in development, whereas neonatal lungs show extensive pulmonary hemorrhage in the alveolar region. No significant histopathological changes occur in other tissues. No remarkable ultrastructural differences are detected between wild type and null lungs. The membranes of a subset of bronchiolar epithelial cells are stained with lectins from Phaseolus vulgaris (leukoagglutinin and erythroagglutinin) and Datura stramonium in wild type lungs, but this staining disappears in lungs from null mice. Mass spectrometry of N-glycans from different tissues shows no significant changes in global N-glycans of null mice. Therefore, only a few glycoproteins required for normal lung function depend on 1,2-mannosidase IB for maturation. There are no apparent differences in the expression of several lung epithelial cell and endothelial cell markers between null and wild type mice. The 1,2-mannosidase IB null phenotype differs from phenotypes caused by ablation of other enzymes in N-glycan biosynthesis and from other mouse gene disruptions that affect pulmonary development and function.

Received for publication, September 7, 2006 , and in revised form, October 31, 2006.

^* This work was supported by the Canadian Institutes of Health Research (to A. H. and N. G. S.) and by the Mizutani Foundation (to A. H.). Work at the Imperial College was supported by the Biotechnology and Biological Sciences Research Council and the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: 3655 Promenade Sir William Osler, Montréal, Québec H3G 1Y6, Canada. Tel.: 514-398-3533; Fax: 514-398-6769; E-mail: annette.herscovics{at}mcgill.ca.

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