Secretory cell hyperplasia and defects in Notch activity in a mouse model of leukocyte adhesion deficiency type II.
OBJECTIVE
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.
Waterhouse
Christopher C M
CC
Department of Paediatrics, Division of Paediatric Gastroenterology, Gastrointestinal Research Group, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada. chris.waterhouse@albertahealthservices.ca
Johnson
Steven
S
Phillipson
Mia
M
Zbytnuik
Lori
L
Petri
Björn
B
Kelly
Margaret
M
Lowe
John B
JB
Kubes
Paul
P
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002238:Carbohydrate Epimerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004195:Disease Models, Animal; D005643:Fucose / Q000008:administration & dosage / Q000172:deficiency; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D005838:Genotype; D020397:Goblet Cells / Q000378:metabolism* / Q000473:pathology; D006836:Hydro-Lyases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006965:Hyperplasia; D007082:Ileum / Q000378:metabolism* / Q000473:pathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D036904:Leukocyte Rolling; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018715:Microscopy, Video; D019879:Paneth Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015430:Weight Gain
D004040:Dietary Carbohydrates; D051880:Receptors, Notch; D005643:Fucose; D006836:Hydro-Lyases; C044971:GDPmannose 4,6-dehydratase; D002238:Carbohydrate Epimerases