Secretory cell hyperplasia and defects in Notch activity in a mouse model of leukocyte adhesion deficiency type II.

BACKGROUND & AIMS: Leukocyte adhesion deficiency II (LAD II) is a rare condition caused by defective protein fucosylation, causing decreased leukocyte rolling, psychomotor retardation, and poor growth. The ligand-binding activity of Notch, a gastrointestinal signaling protein, depends on O-fucosylation. We investigated Notch signaling and intestinal epithelial architecture in a mouse model of LAD II. METHODS: Mice lacking 3,5-epimerase/4-reductase (FX) or FX(-/-) bone marrow chimeras (with either wild-type or FX(-/-) bone marrow) were maintained on a fucose-free diet. Intestinal secretory epithelial cells were quantified by histology and immunohistochemistry. Reverse transcription-polymerase chain reaction and immunoblot analyses were used to detect Notch-regulated genes in isolated crypt epithelium. Intestinal leukocyte-endothelial interaction was quantified by intravital microscopy. The intestinal epithelium of 2-week-old FX(-/-) mice was transfected with an adenoviral vector expressing a constitutively active form of Notch. RESULTS: FX(-/-) mice rapidly exhibited secretory epithelial cell hyperplasia, reduced cell proliferation, and altered epithelial gene expression patterns consistent with reduced Notch signaling. These effects were reversed when mice were given dietary fucose or by adenoviral transfection of the intestinal epithelium with the Notch intracellular domain. CONCLUSIONS: In a mouse model of LAD II, secretory cell hyperplasia occurs in the small intestine and colon; these effects depend on Notch signaling. Defects in Notch signaling might therefore be involved in the pathogenesis of this rare pediatric condition.