Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development
Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development
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DOI：
10.1128/mcb.21.8.2906-2917.2001
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发表时间：
2001-04-01
影响因子：
5.3
通讯作者：
Pawson, T
中科院分区：
文献类型：
--
作者：
Vogel, WF;Aszódi, A;Pawson, T
各种类型的胶原蛋白已被鉴定为两种哺乳动物盘状结构域受体酪氨酸激酶DDR 1和DDR2的潜在配体。在这里，我们使用的重组融合蛋白之间的胞外结构域的DDR 1和碱性磷酸酶，以检测特定的受体结合位点在小鼠发育过程中，DDR 1结合活性的主要网站，配体表达的指示，被发现在骨骼，皮肤和泌尿生殖道。植入期间子宫中和妊娠期间乳腺中的配体表达与DDR 1受体的表达共定位。通过基因靶向产生DDR 1缺失小鼠产生了纯合突变动物，其存活但尺寸小于对照同窝仔。大多数突变雌性由于缺乏适当的胚泡植入子宫壁而不能生育后代，当植入发生时，突变的雌性不能泌乳。组织学分析表明，肺泡上皮细胞未能分泌乳蛋白进入乳腺腔。哺乳缺陷似乎是由乳腺导管的过度增生和异常分支引起的。这些结果表明，DDR 1是乳腺导管形态发生过程中基质-上皮相互作用的关键介质。
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.