Immunohistochemical analysis of Sonic hedgehog signalling in normal human urinary tract development
Immunohistochemical analysis of Sonic hedgehog signalling in normal human urinary tract development
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DOI：
10.1111/j.1469-7580.2007.00808.x
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发表时间：
2007-11-01
影响因子：
2.4
通讯作者：
Woolf, Adrian S.
中科院分区：
文献类型：
--
作者：
Jenkins, Dagan;Winyard, Paul J. D.;Woolf, Adrian S.
对小鼠突变体的研究表明，Sonic Hedgehog (SHH) 信号在形成尿路内多个位点的形态发生和分化中具有功能性作用，并且已经报道了具有破坏 SHH 信号传导的突变的人类尿路畸形。然而，关于正常人类泌尿道发育中 SHH 和相关信号基因的表达，只有极其稀疏和零碎的信息。我们使用免疫组织化学证明 SHH 蛋白定位于发育中的正常人的不同尿路上皮、新生膀胱的尿路上皮和肾髓质集合管中。 SHH 转导蛋白 Patched (PTCH) 和 Smoothened (SMO) 的表达模式与泌尿生殖窦逼尿肌平滑肌分化相关的长程旁分泌信号一致。在发育中的肾脏中，SHH 和 PTCH 在 16-26 周期间在集合系统的上皮细胞中表达 - 令人惊讶的是，没有检测到 SMO。与 SHH 表达下调的 28 周样本相比，26 周时的细胞增殖和 Cyclin B1 免疫组织化学分析与 SHH 和 PTCH 可能通过独立于 SMO 调节 Cyclin B1 的亚细胞定位来影响髓质集合管生长的观点一致。总的来说，这些描述性结果产生了关于人类尿路发育中 SHH 信号转导的新假设，并有助于解释 SHH 通路突变个体中注意到的各种尿路畸形表型。
Studies of mouse mutants have demonstrated that Sonic hedgehog (SHH) signalling has a functional role in morphogenesis and differentiation at multiple sites within the forming urinary tract, and urinary tract malformations have been reported in humans with mutations that disrupt SHH signalling. However, there is only strikingly sparse and fragmentary information about the expression of SHH and associated signalling genes in normal human urinary tract development. We used immunohistochemistry to demonstrate that SHH protein was localised in distinct urinary tract epithelia in developing normal humans, in the urothelium of the nascent bladder and in kidney medullary collecting ducts. The expression patterns of the SHH-transducing proteins Patched (PTCH) and Smoothened (SMO) were consistent with long-range paracrine signalling associated with detrusor smooth muscle differentiation in the urogenital sinus. In the developing kidney, SHH and PTCH were expressed in epithelia of the collecting system between 16-26 weeks - surprisingly, SMO was not detected. Analysis of cell proliferation and Cyclin B1 immunohistochemistry at 26 weeks, as compared with a 28 week sample in which SHH expression was down-regulated, was consistent with the idea that SHH and PTCH might influence medullary collecting duct growth by regulating the subcellular localisation of Cyclin B1 independently of SMO. Collectively, these descriptive results generate new hypotheses regarding SHH signal transduction in human urinary tract development and help to explain the varied urinary tract malformation phenotypes noted in individuals with mutations in the SHH pathway.