Zebrafish nephrogenesis is regulated by interactions between retinoic acid, mecom, and Notch signaling.
Zebrafish nephrogenesis is regulated by interactions between retinoic acid, mecom, and Notch signaling.
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DOI：
10.1016/j.ydbio.2013.11.021
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发表时间：
2014-02-01
影响因子：
2.7
通讯作者：
Wingert, Rebecca A.
中科院分区：
文献类型：
--
作者：
Li, Yue;Cheng, Christina N.;Verdun, Valerie A.;Wingert, Rebecca A.
斑马鱼的原肾提供了一个保守的模型来研究肾脏的发展，特别是描绘了知之甚少的过程中，肾单位段模式和细胞类型的选择是如何建立的。斑马鱼肾单位分为不同的上皮区域，包括一系列的近端和远端小管段，这是由嵌入运输上皮细胞和多纤毛细胞（MCC）。以前的研究表明，视黄酸（RA）区域化肾祖细胞领域的近端和远端域和Notch信号后来抑制MCC分化，但这些途径的进一步了解仍然是未知的。转录因子mecom（mds 1/evi 1复合物）在肾祖细胞中广泛表达，随后标记远端小管。在这里，我们表明，mecom是必要的，以形成远端小管，并限制近端小管的形成和MCC的命运选择。我们发现，mecom和RA有相反的作用，在图案离散的近端和远端段。此外，我们发现RA是MCC形成所必需的，并且RA促进MCC命运选择的一种机制是抑制mecom。接下来，我们确定了mecom和Notch信号传导之间的上位关系，其通过侧抑制限制了MCC命运选择。用γ-分泌酶抑制剂DAPT消除Notch信号传导揭示Notch和mecom在阻断MCC形成方面不具有累加效应，表明它们在相同的途径中起作用。Notch信号传导效应子Notch胞内结构域（NICD）的异位表达挽救了mecom morphant中MCC的扩增，表明mecom在上游起作用以诱导Notch信号传导。这些研究结果表明，mecom和RA仲裁proximodistal节段域的模型，而MCC的命运是由一个复杂的相互作用，其中RA抑制mecom，和mecom促进Notch，tiximodistal MCC的数量调制。总之，我们的研究揭示了几个重要的和新的机制，控制原肾发育的斑马鱼。
The zebrafish pronephros provides a conserved model to study kidney development, in particular to delineate the poorly understood processes of how nephron segment pattern and cell type choice are established. Zebrafish nephrons are divided into distinct epithelial regions that include a series of proximal and distal tubule segments, which are comprised of intercalated transporting epithelial cells and multiciliated cells (MCC). Previous studies have shown that retinoic acid (RA) regionalizes the renal progenitor field into proximal and distal domains and that Notch signaling later represses MCC differentiation, but further understanding of these pathways has remained unknown. The transcription factor mecom (mds1/evi1 complex) is broadly expressed in renal progenitors, and then subsequently marks the distal tubule. Here, we show that mecom is necessary to form the distal tubule and to restrict both proximal tubule formation and MCC fate choice. We found that mecom and RA have opposing roles in patterning discrete proximal and distal segments. Further, we discovered that RA is required for MCC formation, and that one mechanism by which RA promotes MCC fate choice is to inhibit mecom. Next, we determined the epistatic relationship between mecom and Notch signaling, which limits MCC fate choice by lateral inhibition. Abrogation of Notch signaling with the y-secretase inhibitor DAPT revealed that Notch and mecom did not have additive effects in blocking MCC formation, suggesting that they function in the same pathway. Ectopic expression of the Notch signaling effector, Notch intracellular domain (NICD), rescued the expansion of MCCs in mecom morphants, indicating that mecom acts upstream to induce Notch signaling. These findings suggest a model in which mecom and RA arbitrate proximodistal segment domains, while MCC fate is modulated by a complex interplay in which RA inhibition of mecom, and mecom promotion of Notch, titrates MCC number. Taken together, our studies have revealed several essential and novel mechanisms that control pronephros development in the zebrafish.
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影响因子：
64.5
作者：
Duester G
通讯作者：
Duester G
影响因子：
4.5
作者：
Ma, Ming;Jiang, Yun-Jin
通讯作者：
Jiang, Yun-Jin
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4.8
作者：
Alliston, T;Ko, TC;Derynck, R
通讯作者：
Derynck, R
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1.2
作者：
Mead, PE;Parganas, E;Ihle, JN
通讯作者：
Ihle, JN
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13.6
作者：
Naylor, Richard W.;Przepiorski, Aneta;Davidson, Alan J.
通讯作者：
Davidson, Alan J.