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      Localization of Discoidin Domain Receptors in Rat Kidney

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          Background/Aim: The discoidin domain receptors (DDRs) DDR1 and DDR2 are cardinal members of a receptor tyrosine kinase subfamily, activated by collagens. They are candidate effectors in tissue injury and fibrosis. We investigated the DDR expression in normal and remnant rat kidneys. Methods: The DDR expression in kidney and other tissues was examined by indirect immunofluorescence, immunoblotting, and ribonuclease protection assays. The expression patterns in remnant and control kidneys were compared at 2-, 4-, and 8-week time points, following induction of injury. Results: DDR1 is expressed in basolateral membranes of select nephron segments, from the connecting tubule to the renal papilla. DDR2 is expressed in apical membranes of select nephron segments, from the loop of Henle to the macula densa. The DDR1 protein expression is upregulated within the glomeruli of remnant kidneys. The distribution of DDR2 in remnant kidneys is similar to that in controls. The DDR mRNA levels in remnant and control kidneys were not significantly different, at any time point. Conclusions: The DDR1 localization in the rat kidney is consistent with roles in cell-matrix interactions. Upregulation within glomeruli of remnant kidneys suggests the possibility of additional roles in kidney injury. The DDR2 localization in adult rat kidneys is inconsistent with roles in cell-matrix interactions.

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          Most cited references 5

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          Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development.

          Various types of collagen have been identified as potential ligands for the two mammalian discoidin domain receptor tyrosine kinases, DDR1 and DDR2. Here, we used a recombinant fusion protein between the extracellular domain of DDR1 and alkaline phosphatase to detect specific receptor binding sites during mouse development. Major sites of DDR1-binding activity, indicative of ligand expression, were found in skeletal bones, the skin, and the urogenital tract. Ligand expression in the uterus during implantation and in the mammary gland during pregnancy colocalized with the expression of the DDR1 receptor. The generation of DDR1-null mice by gene targeting yielded homozygous mutant animals that were viable but smaller in size than control littermates. The majority of mutant females were unable to bear offspring due to a lack of proper blastocyst implantation into the uterine wall. When implantation did occur, the mutant females were unable to lactate. Histological analysis showed that the alveolar epithelium failed to secrete milk proteins into the lumen of the mammary gland. The lactational defect appears to be caused by hyperproliferation and abnormal branching of mammary ducts. These results suggest that DDR1 is a key mediator of the stromal-epithelial interaction during ductal morphogenesis in the mammary gland.
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            Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons.

            In the developing cerebellum, granule neuron axon outgrowth is a key step toward establishing proper connections with Purkinje neurons, the principal output neuron of the cerebellum. During a search for genes that function in this process, we identified a receptor tyrosine kinase discoidin domain receptor 1 (DDR1) expressed in granule cells throughout their development. Overexpression of a dominant-negative form of DDR1 in immature granule cells results in severe reduction of neurite outgrowth in vitro, in dissociated primary culture, and in vivo, in organotypic slices of neonatal cerebellum. Granule cells that fail to extend axons are positive for differentiation markers such as TAG-1 and the neuron-specific class III beta-tubulin, suggesting that development is affected after granule cells commit to terminal differentiation. DDR1 activation appears to be mediated by its ligand, collagen, which is localized to the pial layer of the developing cerebellum, thereby leading to granule cell parallel fiber extension. Our results therefore indicate that collagen-DDR1 signaling is essential for granule neuron axon formation and further suggest a unique role of pia in cerebellar cortex histogenesis.
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              Expression of discoidin domain receptor 1 tyrosine kinase on the human bronchial epithelium.

               M Ando,  T Suda,  M Suga (2001)
              Discoidin domain receptor 1 (DDR1) tyrosine kinases constitute a novel family of receptors characterized by a unique structure in the ectodomain (discoidin-I domain). The DDR1 ligand is the extracellular matrix protein collagen. To identify receptor tyrosine kinases (RTKs) involved in control of growth and differentiation of human bronchial epithelial (HBE) cells, a polymerase chain reaction-based search for RTKs in HBE cells was performed. DDR1 was the most abundant clone identified. Northern analysis detected a 3.6 kb DDR1 messenger ribonucleic acid (mRNA) expressed in HBE cells and transformed HBE lines, BET-1A and BEAS-2B. In addition, fluorescence-activated cell sorter (FACS) analyses using an anti-DDR1 antibody showed that DDR1 was expressed on HBE cells and two HBE lines. Immunohistochemical staining using human bronchial tissue demonstrated that DDR1 was mainly expressed at the basolateral cell surface of the bronchial epithelium. Furthermore, immunostaining of type IV collagen, a major component of the basement membrane, clearly showed that the basement membrane was closely attached to the basal surface of the bronchial epithelium. Since collagen binds to and activates discoidin domain receptor 1 tyrosine kinase, colocalization of discoidin domain receptor 1 and its ligand type IV collagen demonstrates a potential interaction of discoidin domain receptor 1 on the bronchial epithelium with type IV collagen. Further study of this interaction may define the functional significance of the collagen-discoidin domain receptor 1 signalling pathway in health and in disease.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                June 2004
                17 November 2004
                : 97
                : 2
                : e62-e70
                Division of Renal Diseases and Hypertension, Department of Medicine, University of Minnesota, Minneapolis,Minn., USA
                78407 Nephron Exp Nephrol 2004;97:e62–e70
                © 2004 S. Karger AG, Basel

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                Figures: 6, References: 27, Pages: 1
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