Type XIII collagen is a type II transmembrane protein found at sites of cell adhesion. Transgenic mouse lines were generated by microinjection of a DNA construct directing the synthesis of truncated a1(XIII) chains. Shortened a1(XIII) chains were synthesized by ®bro-blasts from mutant mice, and the lack of intracellular accumulation in immuno¯uorescent staining of tissues suggested that the mutant molecules were expressed on the cell surface. Transgene expression led to fetal lethality in offspring from heterozygous mating with two distinct phenotypes. The early phenotype fetuses were aborted by day 10.5 of development due to a lack of fusion of the chorionic and allantoic membranes. The late phenotype fetuses were aborted by day 13.5 of development and displayed a weak heartbeat, defects of the adherence junctions in the heart with detachment of myo®laments and abnormal staining for the adherence junction component cadherin. Decreased microvessel formation was observed in certain regions of the fetus and the placenta. These results indicate that type XIII collagen has an important role in certain adhesive interactions that are necessary for normal development. Keywords: collagen/fetal lethality/placentation/transgenic mice/vascularization IntroductionThe collagen superfamily of proteins consists of >19 types of collagen and several other proteins with collagen-like domains (Vuorio and de Crombrugghe, 1990;Prockop and Kivirikko, 1995). Type XIII collagen and type XVII collagen form a subfamily of membrane-bound collagens (Pihlajaniemi and Rehn, 1995). Type XIII collagen consists of three collagenous domains (COL1±3) separated and¯anked by four non-collagenous domains (NC1±4) (Pihlajaniemi and Tamminen, 1990). It is predicted that the structures of the COL1, NC2 and COL3 domains of the human and mouse type XIII collagen chains are affected by alternative splicing (Pihlajaniemi and Tamminen, 1990;Tikka et al., 1991;Juvonen and Pihlajaniemi, 1992;Juvonen et al., 1992Juvonen et al., , 1993Peltonen et al., 1997).Type XIII collagen produced in insect cells forms a1(XIII) homotrimers, and the three collagenous domains fold into a stable triple helical conformation (Snellman et al., 2000a). The N-terminal NC1 domain contains a highly hydrophobic transmembrane domain, and the type XIII collagen molecules reside on the plasma membrane of cells in a`type II' orientation with a short N-terminal cytosolic portion, a transmembrane domain and an extensive collagenous ectodomain (Snellman et al., 2000b). Sequences that are important for the association of the three a1(XIII) chains reside in the N-terminal region, and triple helix formation is thought to proceed from the N-terminus to the C-terminus, in the opposite orientation to that known to occur in the ®brillar collagens (Snellman et al., 2000b). The ligands of type XIII collagen are not known, but recent studies with recombinant protein demonstrate that it interacts strongly with the I-domain of a1 integrin (Nykvist et al., 2000).Immunohistochemical studies of mature human...
Epithelial cells of mucosal surfaces are critical for maintaining immune homeostasis by aiding in the discrimination of pathogenic and commensal microorganisms and modulating the activities of antigen-presenting cells and lymphocytes. Functional breakdowns resulting in chronic infection and inflammation are associated with the development of hematologic and solid neoplasms for which detailed pathogenetic mechanisms are poorly understood. Mice heterozygous for a transgene Col13a1 del expressing a mutant collagen XIII developed clonal mature B-cell lineage lymphomas originating in mesenteric lymph nodes (MLN). The tumors were associated with T cells and macrophages. The incidence of disease was reduced 2-fold in transgenic mice raised under specific pathogen-free conditions, suggesting a role for infectious agents. The lymphomas did not express the mutant collagen XIII, indicating that its influence on tumorigenesis was B-cell extrinsic and likely to be associated with collagen XIII-positive tissues drained by the MLN. Studies of the small intestines of transgenic mice showed that the subepithelial basement membranes (BM) were highly abnormal and that they exhibited heightened expression of genes involved in immune responses. These results define collagen XIII-dependent maintenance of the intestinal BM as a previously unappreciated component of immune responses and a critical determinant of cancer susceptibility. [Cancer Res 2008;68(24):10324-32]
Overexpression of type XIII collagen molecules with an 83-amino-acid residue in-frame deletion of part of the ectodomain leads to fetal lethality in Col13a1COL2del transgenic mice. We characterize here the functional disturbances in the cardiovascular system of mouse fetuses overexpressing mutant type XIII collagen. Doppler ultrasonography was performed at 12.5 days of gestation on 33 fetuses resulting from heterozygous matings of seven female mice and on 16 fetuses from two matings between heterozygous and wild-type mice. Nine fetuses had atrioventricular valve regurgitation (AVVR), and all of them were transgene-positive. The fetuses with AVVR had a lower outflow mean velocity (Vmean; P<0.005) and a greater proportion of isovolumetric relaxation time (IRT%) in the cardiac cycle (P<0.0001) than those without AVVR, and their ductus venosus pulsatility indices for veins (DV PIV) and the umbilical artery pulsatility indices were increased. A positive correlation was found between IRT% and DV PIV, and a negative correlation was seen between outflow V(mean) and DV PIV. Morphological analysis of the heart revealed no differences between the two groups of fetuses, but histological analysis showed the trabeculation of the ventricles to be reduced and the myocardium to be thinner in the fetuses with AVVR. Based on in situ hybridization, type XIII collagen mRNAs were normal constituents of these structures. Moreover, a positive correlation was found between outflow Vmean and myocardial thickness. IRT% and DV PIV correlated negatively with myocardial thickness. Thus, overexpression of mutant type XIII collagen results in mid-gestation cardiac dysfunction in mouse fetuses, and these disturbances in cardiac function may lead to death in utero.
Supplementary Table 2 from A Mutant Collagen XIII Alters Intestinal Expression of Immune Response Genes and Predisposes Transgenic Mice to Develop B-Cell Lymphomas
Supplementary Table 1 from A Mutant Collagen XIII Alters Intestinal Expression of Immune Response Genes and Predisposes Transgenic Mice to Develop B-Cell Lymphomas
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