Notch2 Activation in the Embryonic Kidney Depletes Nephron Progenitors
Notch2 Activation in the Embryonic Kidney Depletes Nephron Progenitors
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DOI：
10.1681/asn.2009040353
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发表时间：
2010-05-01
影响因子：
13.6
通讯作者：
Nishinakamura, Ryuichi
中科院分区：
文献类型：
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作者：
Fujimura, Sayoko;Jiang, Qing;Nishinakamura, Ryuichi
Wnt4和Notch2的连续激活产生了来自后肾间充质的肾单位。间充质到上皮的转变需要WNT4，而近端肾单位(肾小球和近端小管的上皮细胞)的正常发育需要Notch2。然而，目前尚不清楚Notch2是否直接决定了近端肾单位的命运。在这里，我们在后肾间充质的含SIX2的肾单位祖细胞中产生了一种Notch2激活的突变小鼠。Notch2的激活不会使细胞的命运偏向近端的肾单位，但会导致严重的肾脏发育不全和SIX2阳性祖细胞的枯竭。我们观察到WNT4的异位表达和过早的小管形成，类似于SIX2缺陷小鼠的表型。前体细胞中Notch2的激活可能通过Hesr基因抑制了SIX2的上游调节因子Pax2。综上所述，这些数据表明Notch2和Wnt4之间存在正反馈环路，Notch2通过关闭未分化祖细胞的维持而稳定而不是决定肾单位的命运，从而耗尽这一群体。
Successive activation of Wnt4 and Notch2 generates nephrons from the metanephric mesenchyme. Mesenchymal-to-epithelial transition requires Wnt4, and normal development of the proximal nephron (epithelia of glomeruli and proximal tubules) requires Notch2. It is unknown, however, whether Notch2 dictates the fate of the proximal nephron directly. Here, we generated a mutant strain of mice with activated Notch2 in Six2-containing nephron progenitor cells of the metanephric mesenchyme. Notch2 activation did not skew the cell fate toward the proximal nephron but resulted in severe kidney dysgenesis and depletion of Six2-positive progenitors. We observed ectopic expression of Wnt4 and premature tubule formation, similar to the phenotype of Six2-deficient mice. Activation of Notch2 in the progenitor cells suppressed Pax2, an upstream regulator of Six2, possibly through Hesr genes. Taken together, these data suggest that a positive feedback loop exists between Notch2 and Wnt4, and that Notch2 stabilizes, rather than dictates, nephron fate by shutting down the maintenance of undifferentiated progenitor cells, thereby depleting this population.