BMP7 promotes proliferation of nephron progenitor cells via a JNK-dependent mechanism
BMP7 promotes proliferation of nephron progenitor cells via a JNK-dependent mechanism
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DOI：
10.1242/dev.036335
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发表时间：
2009-11-01
期刊：
影响因子：
4.6
通讯作者：
Oxburgh, Leif
中科院分区：
文献类型：
--
作者：
Blank, Ulrika;Brown, Aaron;Oxburgh, Leif
胚胎发育过程中肾单位的迭代形成依赖于肾发生过程中祖细胞的持续补充。定义维持和调节该祖细胞库的分子机制对于理解发育和再生环境中的肾发生至关重要。肾单位祖细胞的维持绝对依赖于 BMP7 信号传导，并且 Bmp7 缺失小鼠表现出祖细胞的快速丧失。然而，BMP7 下游的信号转导机制以及精确的靶细胞仍不清楚。使用新型原代祖细胞分离系统，我们研究了 BMP7 引发的信号转导和生物学结果。我们发现 BMP7 直接快速激活肾单位祖细胞中的 JNK 信号传导，导致 Jun 和 ATF2 转录因子磷酸化。这种信号传导导致细胞周期蛋白 D3 的积累以及随后 PAX2(+) 祖细胞的增殖，与 Bmp7 缺失肾脏中观察到的肾单位祖细胞的损失呈负相关。 Jun 和 ATF2 的激活在 Bmp7 缺失的肾脏中严重减弱，提供了重要的体内相关性。因此，BMP7 通过激活 JNK 信号通路直接促进肾单位祖细胞的增殖。
The iterative formation of nephrons during embryonic development relies on continual replenishment of progenitor cells throughout nephrogenesis. Defining molecular mechanisms that maintain and regulate this progenitor pool is essential to understanding nephrogenesis in developmental and regenerative contexts. Maintenance of nephron progenitors is absolutely dependent on BMP7 signaling, and Bmp7-null mice exhibit rapid loss of progenitors. However, the signal transduction machinery operating downstream of BMP7 as well as the precise target cell remain undefined. Using a novel primary progenitor isolation system, we have investigated signal transduction and biological outcomes elicited by BMP7. We find that BMP7 directly and rapidly activates JNK signaling in nephron progenitors resulting in phosphorylation of Jun and ATF2 transcription factors. This signaling results in the accumulation of cyclin D3 and subsequent proliferation of PAX2(+) progenitors, inversely correlating with the loss of nephron progenitors seen in the Bmp7-null kidney. Activation of Jun and ATF2 is severely diminished in Bmp7-null kidneys, providing an important in vivo correlate. BMP7 thus promotes proliferation directly in nephron progenitors by activating the JNK signaling circuitry.