Sajithlal Gangadharan, Zou Dan, Silvius Derek, Xu Pin-Xian
McLaughlin Research Institute for Biomedical Sciences, Great Falls, MT 59405, USA.
Dev Biol. 2005 Aug 15;284(2):323-36. doi: 10.1016/j.ydbio.2005.05.029.
Although it is well established that the Gdnf-Ret signal transduction pathway initiates metanephric induction, no single regulator has yet been identified to specify the metanephric mesenchyme or blastema within the intermediate mesoderm, the earliest step of metanephric kidney development and the molecular mechanisms controlling Gdnf expression are essentially unknown. Previous studies have shown that a loss of Eya 1 function leads to renal agenesis that is a likely result of failure of metanephric induction. The studies presented here demonstrate that Eya 1 specifies the metanephric blastema within the intermediate mesoderm at the caudal end of the nephrogenic cord. In contrast to its specific roles in metanephric development, Eya 1 appears dispensable for the formation of nephric duct and mesonephric tubules. Using a combination of null and hypomorphic Eya 1 mutants, we now demonstrated that approximately 20% of normal Eya 1 protein level is sufficient for establishing the metanephric blastema and inducing the ureteric bud formation but not for its normal branching. Using Eya 1, Gdnf, Six 1 and Pax 2 mutant mice, we show that Eya 1 probably functions at the top of the genetic hierarchy controlling kidney organogenesis and it acts in combination with Six 1 and Pax 2 to regulate Gdnf expression during UB outgrowth and branching. These findings uncover an essential function for Eya 1 as a critical determination factor in acquiring metanephric fate within the intermediate mesoderm and as a key regulator of Gdnf expression during ureteric induction and branching morphogenesis.
尽管已充分证实Gdnf-Ret信号转导通路启动后肾诱导，但尚未鉴定出单一调节因子来确定中肾间充质或尾芽，这是后肾发育的最早步骤，而控制Gdnf表达的分子机制基本上尚不清楚。先前的研究表明，Eya 1功能丧失会导致肾发育不全，这可能是后肾诱导失败的结果。本文提出的研究表明，Eya 1在肾发生索尾端的中肾间充质中确定后肾芽。与它在后肾发育中的特定作用相反，Eya 1对于肾管和中肾小管的形成似乎是可有可无的。使用无效和低表达Eya 1突变体的组合，我们现在证明，正常Eya 1蛋白水平的约20%足以建立后肾芽并诱导输尿管芽形成，但不足以使其正常分支。使用Eya 1、Gdnf、Six 1和Pax 2突变小鼠，我们表明Eya 1可能在控制肾脏器官发生的遗传层次结构的顶端起作用，并且它与Six 1和Pax 2共同作用，在输尿管芽生长和分支过程中调节Gdnf表达。这些发现揭示了Eya 1作为中肾间充质内获得后肾命运的关键决定因素以及输尿管诱导和分支形态发生过程中Gdnf表达的关键调节因子的重要功能。
