The hedgehog signal induced modulation of bone morphogenetic protein signaling: an essential signaling relay for urinary tract morphogenesis.
The hedgehog signal induced modulation of bone morphogenetic protein signaling: an essential signaling relay for urinary tract morphogenesis.
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DOI：
10.1371/journal.pone.0042245
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yamada G
中科院分区：
文献类型：
--
作者：
Haraguchi R;Matsumaru D;Nakagata N;Miyagawa S;Suzuki K;Kitazawa S;Yamada G
先天性泌尿道疾病在婴儿中常见。这类疾病表现出许多发育异常，如输尿管积水和肾积水。尽管一些生长因子信号基因的转基因小鼠模型复制了尿液表型，但致病机制仍然不清楚。先前的研究表明，外生殖器和膀胱中的一部分细胞来源于在早期发育阶段接受Hedgehog（Hh）信号的泄殖腔周围间充质细胞。我们推测，这种祖细胞的缺陷，引起尿路组织，可能是这些疾病的原因。为了阐明上尿路畸形的致病机制，我们分析了一系列Sonic hedgehog（Shh）缺陷小鼠。Shh−/−显示输尿管积水和肾盂积水表型，并降低了几种发育标记物的表达。此外，我们建议，Shh调制在早期胚胎阶段是负责这样的表型通过分析Shh条件突变体。Hh反应细胞的组织贡献分析表明，泄殖腔周围的间充质细胞，它收到了泄殖腔上皮分泌的Hh信号，可以有助于输尿管间充质。Hh信号的获得和丧失功能突变体揭示了Hh信号和骨形态发生蛋白（Bmp）信号之间的相关性。最后，在Hh反应细胞系中检查了BMP受体IA型（BmprIA）基因的条件性消融。因此，该系统使得分析生长因子信号传递的主要功能成为可能。有缺陷的Hh到BMP信号传递导致严重的尿路表型，Hh反应细胞的数量减少。这项研究确定了泌尿道表型发病的基本胚胎阶段。这些结果表明，Hh-反应性间充质BMP信号传导维持了泄殖腔周围间充质细胞的群体，这对于输尿管和上尿路的发育是必需的。
Congenital diseases of the urinary tract are frequently observed in infants. Such diseases present a number of developmental anomalies such as hydroureter and hydronephrosis. Although some genetically-modified mouse models of growth factor signaling genes reproduce urinary phenotypes, the pathogenic mechanisms remain obscure. Previous studies suggest that a portion of the cells in the external genitalia and bladder are derived from peri-cloacal mesenchymal cells that receive Hedgehog (Hh) signaling in the early developmental stages. We hypothesized that defects in such progenitor cells, which give rise to urinary tract tissues, may be a cause of such diseases. To elucidate the pathogenic mechanisms of upper urinary tract malformations, we analyzed a series of Sonic hedgehog (Shh) deficient mice. Shh−/− displayed hydroureter and hydronephrosis phenotypes and reduced expression of several developmental markers. In addition, we suggested that Shh modulation at an early embryonic stage is responsible for such phenotypes by analyzing the Shh conditional mutants. Tissue contribution assays of Hh-responsive cells revealed that peri-cloacal mesenchymal cells, which received Hh signal secreted from cloacal epithelium, could contribute to the ureteral mesenchyme. Gain- and loss-of-functional mutants for Hh signaling revealed a correlation between Hh signaling and Bone morphogenetic protein (Bmp) signaling. Finally, a conditional ablation of Bmp receptor type IA (BmprIA) gene was examined in Hh-responsive cell lineages. This system thus made it possible to analyze the primary functions of the growth factor signaling relay. The defective Hh-to-Bmp signaling relay resulted in severe urinary tract phenotypes with a decrease in the number of Hh-responsive cells. This study identified the essential embryonic stages for the pathogenesis of urinary tract phenotypes. These results suggested that Hh-responsive mesenchymal Bmp signaling maintains the population of peri-cloacal mesenchyme cells, which is essential for the development of the ureter and the upper urinary tract.
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影响因子：
4.6
作者：
Di Giovanni, Valeria;Alday, Adrian;Rosenblum, Norman D.
通讯作者：
Rosenblum, Norman D.
影响因子：
13.6
作者：
Hartwig, Sunny;Bridgewater, Darren;Rosenblum, Norman D.
通讯作者：
Rosenblum, Norman D.
DOI：
10.1006/bbrc.1997.7124
发表时间：
1997-08-28
影响因子：
3.1
作者：
Feil, R;Wagner, J;Chambon, P
通讯作者：
Chambon, P
DOI：
10.1073/pnas.93.20.10887
发表时间：
1996-10-01
影响因子：
11.1
作者：
Feil, R;Brocard, J;Chambon, P
通讯作者：
Chambon, P
影响因子：
64.8
作者：
Chiang, C;Ying, LTT;Beachy, PA
通讯作者：
Beachy, PA