Michos Odyssé, Panman Lia, Vintersten Kristina, Beier Konstantin, Zeller Rolf, Zuniga Aimée
Developmental Genetics, Dept. of Clinical-Biological Sciences (DKBW University of Basel Medical School, c/o Anatomy Institute, Pestalozzistrasse 20, CH-4056 Basel, Switzerland.
Development. 2004 Jul;131(14):3401-10. doi: 10.1242/dev.01251. Epub 2004 Jun 16.
Epithelial-mesenchymal feedback signaling is the key to diverse organogenetic processes such as limb bud development and branching morphogenesis in kidney and lung rudiments. This study establishes that the BMP antagonist gremlin (Grem1) is essential to initiate these epithelial-mesenchymal signaling interactions during limb and metanephric kidney organogenesis. A Grem1 null mutation in the mouse generated by gene targeting causes neonatal lethality because of the lack of kidneys and lung septation defects. In early limb buds, mesenchymal Grem1 is required to establish a functional apical ectodermal ridge and the epithelial-mesenchymal feedback signaling that propagates the sonic hedgehog morphogen. Furthermore, Grem1-mediated BMP antagonism is essential to induce metanephric kidney development as initiation of ureter growth, branching and establishment of RET/GDNF feedback signaling are disrupted in Grem1-deficient embryos. As a consequence, the metanephric mesenchyme is eliminated by apoptosis, in the same way as the core mesenchymal cells of the limb bud.
上皮-间充质反馈信号传导是多种器官发生过程的关键，如肢体芽发育以及肾脏和肺原基的分支形态发生。本研究证实，骨形态发生蛋白（BMP）拮抗剂gremlin（Grem1）对于在肢体和后肾器官发生过程中启动这些上皮-间充质信号相互作用至关重要。通过基因靶向在小鼠中产生的Grem1无效突变会导致新生儿死亡，原因是缺乏肾脏和肺分隔缺陷。在早期肢体芽中，间充质Grem1是建立功能性顶端外胚层嵴和传播音猬因子形态发生素的上皮-间充质反馈信号传导所必需的。此外，Grem1介导的BMP拮抗作用对于诱导后肾发育至关重要，因为在Grem1缺陷胚胎中输尿管生长的起始、分支以及RET/GDNF反馈信号传导的建立均受到破坏。结果，后肾间充质与肢体芽的核心间充质细胞一样通过凋亡被清除。
