Batourina E, Gim S, Bello N, Shy M, Clagett-Dame M, Srinivas S, Costantini F, Mendelsohn C
Department of Urology, Columbia University, New York, New York, USA.
Nat Genet. 2001 Jan;27(1):74-8. doi: 10.1038/83792.
Mutations or rearrangements in the gene encoding the receptor tyrosine kinase RET result in Hirschsprung disease, cancer and renal malformations. The standard model of renal development involves reciprocal signaling between the ureteric bud epithelium, inducing metanephric mesenchyme to differentiate into nephrons, and metanephric mesenchyme, inducing the ureteric bud to grow and branch. RET and GDNF (a RET ligand) are essential mediators of these epithelial-mesenchymal interactions. Vitamin A deficiency has been associated with widespread embryonic abnormalities, including renal malformations. The vitamin A signal is transduced by nuclear retinoic acid receptors (RARs). We previously showed that two RAR genes, Rara and Rarb2, were colocalized in stromal mesenchyme, a third renal cell type, where their deletion led to altered stromal cell patterning, impaired ureteric bud growth and downregulation of Ret in the ureteric bud. Here we demonstrate that forced expression of Ret in mice deficient for both Rara and Rarb2 (Rara(-/-)Rarb2(-/-)) genetically rescues renal development, restoring ureteric bud growth and stromal cell patterning. Our studies indicate the presence of a new reciprocal signaling loop between the ureteric bud epithelium and the stromal mesenchyme, dependent on Ret and vitamin A. In the first part of the loop, vitamin-A-dependent signals secreted by stromal cells control Ret expression in the ureteric bud. In the second part of the loop, ureteric bud signals dependent on Ret control stromal cell patterning.
编码受体酪氨酸激酶RET的基因发生突变或重排会导致先天性巨结肠症、癌症和肾脏畸形。肾脏发育的标准模型涉及输尿管芽上皮与后肾间充质之间的相互信号传导，输尿管芽上皮诱导后肾间充质分化为肾单位，而后肾间充质诱导输尿管芽生长和分支。RET和GDNF（一种RET配体）是这些上皮-间充质相互作用的重要介质。维生素A缺乏与广泛的胚胎异常有关，包括肾脏畸形。维生素A信号由核视黄酸受体（RARs）转导。我们之前发现，两个RAR基因Rara和Rarb2共定位于肾间质（第三种肾细胞类型），它们的缺失导致间质细胞模式改变、输尿管芽生长受损以及输尿管芽中Ret表达下调。在此我们证明，在同时缺乏Rara和Rarb2（Rara(-/-)Rarb2(-/-)）的小鼠中强制表达Ret可在基因层面挽救肾脏发育，恢复输尿管芽生长和间质细胞模式。我们的研究表明，在输尿管芽上皮和间质之间存在一个新的相互信号传导环路，该环路依赖于Ret和维生素A。在环路的第一部分，间质细胞分泌的维生素A依赖性信号控制输尿管芽中Ret的表达。在环路的第二部分，依赖于Ret的输尿管芽信号控制间质细胞模式。
