John Cochran Veterans Affairs Medical Center, St Louis, MO 63106, USA.
Development. 2010 Sep;137(18):3099-106. doi: 10.1242/dev.037812. Epub 2010 Aug 11.
Development of the metanephric kidney depends on precise control of branching of the ureteric bud. Branching events represent terminal bifurcations that are thought to depend on unique patterns of gene expression in the tip compared with the stalk and are influenced by mesenchymal signals. The metanephric mesenchyme-derived signals that control gene expression at the ureteric bud tip are not well understood. In mouse Sall1 mutants, the ureteric bud grows out and invades the metanephric mesenchyme, but it fails to initiate branching despite tip-specific expression of Ret and Wnt11. The stalk-specific marker Wnt9b and the beta-catenin downstream target Axin2 are ectopically expressed in the mutant ureteric bud tips, suggesting that upregulated canonical Wnt signaling disrupts ureter branching in this mutant. In support of this hypothesis, ureter arrest is rescued by lowering beta-catenin levels in the Sall1 mutant and is phenocopied by ectopic expression of a stabilized beta-catenin in the ureteric bud. Furthermore, transgenic overexpression of Wnt9b in the ureteric bud causes reduced branching in multiple founder lines. These studies indicate that Sall1-dependent signals from the metanephric mesenchyme are required to modulate ureteric bud tip Wnt patterning in order to initiate branching.
后肾原基的发育依赖于输尿管芽分支的精确控制。分支事件代表末端分叉,据认为这些分叉依赖于尖端与干部之间独特的基因表达模式,并且受到间质信号的影响。控制输尿管芽尖端基因表达的后肾间充质衍生信号尚未得到很好的理解。在 Sall1 突变小鼠中,输尿管芽向外生长并侵入后肾间充质,但尽管尖端特异性表达 Ret 和 Wnt11,但其分支仍未能启动。尽管在突变的输尿管芽尖端异位表达了 stalk 特异性标记物 Wnt9b 和β-catenin 的下游靶标 Axin2,但这表明上调的经典 Wnt 信号会破坏该突变体中的输尿管分支。为了支持这一假说,降低 Sall1 突变体中的β-catenin 水平可挽救输尿管阻滞,并通过在输尿管芽中异位表达稳定的β-catenin 来模拟该表型。此外,在输尿管芽中过表达 Wnt9b 可导致多个起始线的分支减少。这些研究表明,Sall1 依赖的后肾间充质信号对于调节输尿管芽尖端 Wnt 模式以启动分支是必需的。