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Molecular and Cellular Biology, April 2001, p. 2906-2917, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2906-2917.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Discoidin Domain Receptor 1 Tyrosine Kinase Has an Essential Role in Mammary Gland Development

Wolfgang F. Vogel,1,* Attila Aszódi,2 Frauke Alves,3 and Tony Pawson1,4

Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5,1 and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8,4 Canada; Department of Experimental Pathology, Lund University Hospital, 22185 Lund, Sweden2; and Department of Hematology and Oncology, University of Göttingen, 37075 Göttingen, Germany3

Received 24 October 2000/Returned for modification 7 December 2000/Accepted 26 January 2001

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.

* Corresponding author. Present address: Georg-Speyer-Haus Institute for Biomedical Research, Johann Wolfgang Goethe Universität Frankfurt, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany. Phone: 49-69-63395 222. Fax: 49-69-63395 297. E-mail: W.Vogel{at}em.uni-frankfurt.de.

Molecular and Cellular Biology, April 2001, p. 2906-2917, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2906-2917.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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