Homeodomain factor Nkx2-3 controls regional expression of leukocyte homing coreceptor MAdCAM-1 in specialized endothelial cells of the viscera.
Regulated emigration of blood-borne leukocytes plays a defining role in lymphoid organ development, immune surveillance, and inflammatory responses. We report here that mice deficient in the homeobox gene Nkx2-3, expressed in developing visceral mesoderm, show a complex intestinal malabsorption phenotype and striking abnormalities of gut-associated lymphoid tissue and spleen suggestive of deranged leukocyte homing. Mutant Peyer's patches were reduced in number and size, intestinal villi contained few IgA(+) plasma cells, and mutant spleens were small and often atrophic, showing fused periarterial lymphoid sheaths, partially merged T and B cell zones, an absent marginal zone, and a dearth of macrophages in red pulp. Semiquantitative RT-PCR analysis and immunohistochemistry revealed down-regulation of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in endothelial cells in which Nkx2-3 is normally expressed. MAdCAM-1 is a member of the immunoglobulin superfamily, acting as an endothelial cell ligand for leukocyte homing receptors L-selectin and alpha4beta7 integrin. Our data suggest a role for a homeodomain factor in establishing the developmental and positional cues in endothelia that regulate leukocyte homing through local control of cellular adhesion and identify MAdCAM-1 as a candidate target gene of Nkx2-3.
Victor Chang Cardiac Research Institute, St. Vincent's Hospital, Darlinghurst, Australia.
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Wang
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Biben
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Robb
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Nassir
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Barnett
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Davidson
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Koentgen
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Tarlinton
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Harvey
D000818:Animals; D001483:Base Sequence; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007136:Immunoglobulins / Q000235:genetics*; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D009088:Mucoproteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D016201:Receptors, Lymphocyte Homing / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014781:Viscera; D029961:Zebrafish Proteins
D015815:Cell Adhesion Molecules; D017931:DNA Primers; D018398:Homeodomain Proteins; D007136:Immunoglobulins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C102935:Nkx2.3 protein, zebrafish; D016201:Receptors, Lymphocyte Homing; D029961:Zebrafish Proteins