Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by a Gata3-Raldh2-Ret molecular network in mice
Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by a Gata3-Raldh2-Ret molecular network in mice
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DOI：
10.1242/dev.056838
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发表时间：
2011-05-15
期刊：
影响因子：
4.6
通讯作者：
Bouchard, Maxime
中科院分区：
文献类型：
--
作者：
Chia, Ian;Grote, David;Bouchard, Maxime
泌尿道的发育取决于一系列复杂的过程，其中输尿管从其在肾管（ND）上的初始分支点移动到其在泄殖腔（原始膀胱和尿道）中的最终插入点。这个成熟过程中的缺陷会导致输尿管错位和肾积水，这是儿童肾脏疾病的常见原因。在这里，我们报告说，插入的ND到泄殖腔是一个未被认识到的，但关键的一步，需要正确定位的输尿管，这取决于Ret信号。Ret突变小鼠在出生时的分析揭示了肾积水和输尿管成熟缺陷，我们的研究结果表明，异常是由延迟插入的ND，至少部分。我们在缺乏Gata 3或Raldh 2的突变体中发现了类似的一组畸形。我们发现，这些因素的作用是并行调节ND插入通过Ret。野生型胚胎中ND延伸的形态学分析揭示了在Ret，Gata 3或Raldh 2突变体胚胎中未检测到的ND尖端处的精细细胞突起，这表明这些突起通常对于与泄殖腔的融合可能是重要的。总之，我们的研究揭示了一种新的视网膜依赖性事件，ND插入，当异常时，可导致梗阻和出生时肾盂积水; ND缺陷是否是人类类似类型尿路异常的基础是一个有趣的可能性。
Urinary tract development depends on a complex series of events in which the ureter moves from its initial branch point on the nephric duct (ND) to its final insertion site in the cloaca (the primitive bladder and urethra). Defects in this maturation process can result in malpositioned ureters and hydronephrosis, a common cause of renal disease in children. Here, we report that insertion of the ND into the cloaca is an unrecognized but crucial step that is required for proper positioning of the ureter and that depends on Ret signaling. Analysis of Ret mutant mice at birth reveals hydronephrosis and defective ureter maturation, abnormalities that our results suggest are caused, at least in part, by delayed insertion of the ND. We find a similar set of malformations in mutants lacking either Gata3 or Raldh2. We show that these factors act in parallel to regulate ND insertion via Ret. Morphological analysis of ND extension in wild-type embryos reveals elaborate cellular protrusions at ND tips that are not detected in Ret, Gata3 or Raldh2 mutant embryos, suggesting that these protrusions may normally be important for fusion with the cloaca. Together, our studies reveal a novel Ret-dependent event, ND insertion, that, when abnormal, can cause obstruction and hydronephrosis at birth; whether ND defects underlie similar types of urinary tract abnormalities in humans is an interesting possibility.