Homeodomain factor Nkx2-3 controls regional expression of leukocyte homingcoreceptor MAdCAM-1 in specialized endothelial cells of the viscera

Regulated emigration of blood-borne leukocytes plays a defining role in lym phoid organ development, immune surveillance, and inflammatory responses. W e report here that mice deficient in the homeobox gene Nkx2-3, expressed in developing visceral mesoderm, show a complex: intestinal malabsorption phe notype and striking abnormalities of gut-associated lymphoid tissue and spl een suggestive of deranged leukocyte homing. Mutant Peyer's patches were re duced in number and size, intestinal villi contained few IgA(+) plasma cell s, and mutant spleens were small and often atrophic, showing fused periarte rial lymphoid sheaths, partially merged T and B cell zones, an absent margi nal zone, and a dearth of macrophages in red pulp. Semiquantitative RT-PCR analysis and immunohistochemistry revealed down-regulation of mucosal addre ssin cell adhesion molecule-1 (MAdCAM-1) in endothelial cells in which Nkx2 -3 is normally expressed. MAdCAM-1 is a member of the immunoglobulin superf amily, acting as an endothelial cell ligand for leukocyte homing receptors L-selectin and alpha 4 beta 7 integrin. Our data suggest a role for a homeo domain factor in establishing the developmental and positional cues in endo thelia that regulate leukocyte homing through local control of cellular adh esion and identify MAdCAM-1 as a candidate target gene of Nkx2-3. (C) 2000 Academic Press.