Jagged2a-notch signaling mediates cell fate choice in the zebrafish pronephric duct.
Jagged2a-notch signaling mediates cell fate choice in the zebrafish pronephric duct.
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DOI：
10.1371/journal.pgen.0030018
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发表时间：
2007-01-26
期刊：
影响因子：
4.5
通讯作者：
Jiang, Yun-Jin
中科院分区：
文献类型：
--
作者：
Ma, Ming;Jiang, Yun-Jin
原肾是成年哺乳动物肾脏（后肾）的发育模型，也是早期硬骨鱼的功能性肾脏。这些结构和功能元件负责不同的肾功能，例如，血液过滤、废物提取、盐回收和水平衡。在原肾器官发生过程中，细胞分化是在特定位置产生不同细胞类型以完成指定功能的关键步骤。然而，人们对哪些分子调节肾脏不同部位不同细胞类型的分化知之甚少。在斑马鱼远侧原肾管上皮中发现两种类型的上皮细胞，即多纤毛细胞和主细胞。虽然前者的特点是至少有15个顶部本地化的纤毛，并表达centrin 2和rfx 2，后者的特点是由一个单一的初级纤毛和钠泵。多纤毛细胞和主细胞从受精后17.5小时起分化为马赛克模式。Jagged 2a-Notch 1a/Notch 3-Her 9通过侧抑制机制负责这两种细胞类型的特化和图案化。此外，在思维炸弹突变体中观察到多纤毛细胞增生，并且思维炸弹显示与Jagged 2a相互作用并促进其内化。总之，我们的研究结果增加了一个新的范式Notch信号在肾脏发育，即，锯齿状2a-Notch信号调节细胞命运的选择，在肾段，远端前肾管。肾脏是一个复杂的器官，通过维持液体和离子平衡以及处理代谢废物来调节血液稳态。我们使用斑马鱼原肾（一种原始脊椎动物肾脏）来解决肾脏组织如何获得其细胞类型和模式。原肾管上皮细胞有多纤毛细胞和主细胞两种类型，可根据形态和不同标志基因的表达进行区分。在前肾管中，多纤毛细胞和主细胞形成“盐和胡椒”或马赛克图案。使用现有的斑马鱼突变体和敲除技术，我们证明了这两种细胞类型的马赛克模式和分化是通过Notch依赖的侧抑制机制控制的。Notch信号传导已被证明对肾脏发育的其他方面是必不可少的，例如肾小球和小管的形成。在这里，据我们所知的第一次，我们表明，相同的信号通路是需要两个不同的上皮细胞在一个肾段称为远端前肾管的分化。同样的机制很可能在相同的背景下被其他类似的发育过程所采用，以在组织中产生不同的细胞类型。
Pronephros, a developmental model for adult mammalian kidneys (metanephros) and a functional kidney in early teleosts, consists of glomerulus, tubule, and duct. These structural and functional elements are responsible for different kidney functions, e.g., blood filtration, waste extraction, salt recovery, and water balance. During pronephros organogenesis, cell differentiation is a key step in generating different cell types in specific locations to accomplish designated functions. However, it is poorly understood what molecules regulate the differentiation of different cell types in different parts of the kidney. Two types of epithelial cells, multi-cilia cells and principal cells, are found in the epithelia of the zebrafish distal pronephric duct. While the former is characterized by at least 15 apically localized cilia and expresses centrin2 and rfx2, the latter is characterized by a single primary cilium and sodium pumps. Multi-cilia cells and principal cells differentiate from 17.5 hours post-fertilization onwards in a mosaic pattern. Jagged2a-Notch1a/Notch3-Her9 is responsible for specification and patterning of these two cell types through a lateral inhibition mechanism. Furthermore, multi-cilia cell hyperplasia was observed in mind bomb mutants and Mind bomb was shown to interact with Jagged2a and facilitate its internalization. Taken together, our findings add a new paradigm of Notch signaling in kidney development, namely, that Jagged2a-Notch signaling modulates cell fate choice in a nephric segment, the distal pronephric duct. The kidney is a complex organ that regulates blood homeostasis through the maintenance of fluid and ion balance and disposal of metabolic waste. We used zebrafish pronephros, a primordial vertebrate kidney, to address how a kidney tissue acquires its cell types and pattern. Two types of epithelial cells were found in the pronephric duct: multi-cilia cells and principal cells, which could be distinguished based on morphology and expression of different marker genes. In the pronephric duct, the multi-cilia cells and principal cells form a “salt and pepper,” or mosaic, pattern. Using existing zebrafish mutants and a knockdown technique, we demonstrated that the mosaic pattern and differentiation of these two cell types are controlled through a Notch-dependent lateral inhibition mechanism. Notch signaling has been shown to be essential for other aspects of kidney development, such as formation of the glomerulus and the tubule. Here, to our knowledge for the first time, we show that the same signaling pathway is required for the differentiation of two different epithelial cells in a kidney segment known as the distal pronephric duct. The same mechanism is very likely to be employed by other similar developmental processes in the same context to generate distinct cell types in a tissue.
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