Nephron proximal tubule patterning and corpuscles of Stannius formation are regulated by the sim1a transcription factor and retinoic acid in zebrafish
Nephron proximal tubule patterning and corpuscles of Stannius formation are regulated by the sim1a transcription factor and retinoic acid in zebrafish
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DOI：
10.1016/j.ydbio.2014.12.020
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发表时间：
2015-03-01
影响因子：
2.7
通讯作者：
Wingert, Rebecca A.
中科院分区：
文献类型：
--
作者：
Cheng, Christina N.;Wingert, Rebecca A.
建立肾单位节段的机制知之甚少。斑马鱼的胚胎肾，或原肾，是一个简化但保守的遗传模型，以研究这一肾脏发育过程，因为它的肾单位含有类似于其他脊椎动物的部分，包括近曲和直小管（PCT，PST）。斑马鱼的原肾也与斯坦尼厄斯小体（CS）有关，斯坦尼厄斯小体是调节钙和磷酸盐稳态的内分泌腺，但其从肾祖细胞的个体发育在很大程度上是神秘的。在中间中胚层（IM）的斑马鱼肾祖细胞的初始图案涉及形成的吻和尾域，前者依赖于视黄酸（RA）信号，后者被抑制RA水平升高。在这里，使用表达谱，以获得新的见解，肾，我们发现，基因单一的家庭bHLH转录因子1a（sim 1a）是动态表达的肾祖细胞，首先标记的尾部结构域，然后成为限制在近端部分，并最终表现出特定的CS表达。在功能丧失研究中，sim 1a敲除扩大了PCT并消除了PST和CS群体。相反，过表达sim 1a适度扩大PST和CS，而减少PCT。这些结果表明，sim 1a活性是必要的，部分足以诱导PST和CS命运，并表明sim 1a可能抑制PCT命运和/或谈判PCT/PST边界。有趣的是，肾祖细胞中的sim 1a表达结构域对RA水平的改变有反应，这表明RA在肾发生过程中直接或间接地调节sim 1a。用外源性RA处理的sim 1a缺陷胚胎形成主要由PCT片段组成的肾单位，但缺乏在RA处理的野生型中观察到的扩大的PST，表明RA不足以在没有sim 1a表达的情况下拯救PST。或者，当sim 1a敲低暴露于RA抑制剂二乙氨基苯甲醛（DEAB），CS被废除，而不是扩大看到DEAB处理的野生型，揭示CS的形成，在没有sim 1a不能拯救RA生物合成废除。总而言之，这些数据揭示了sim 1a在斑马鱼原肾近端小管和CS模式中以前未被认识到的作用，并且与sim 1a作用于RA下游以减轻这些谱系形成的模型一致。这些发现为指导肾单位发育的遗传途径提供了新的见解，并可能对理解肾脏出生缺陷和肾脏重编程产生影响。(C)2014作者爱思唯尔公司出版
The mechanisms that establish nephron segments are poorly understood. The zebrafish embryonic kidney, or pronephros, is a simplified yet conserved genetic model to study this renal development process because its nephrons contain segments akin to other vertebrates, including the proximal convoluted and straight tubules (PCT, PST). The zebrafish pronephros is also associated with the corpuscles of Stannius (CS), endocrine glands that regulate calcium and phosphate homeostasis, but whose ontogeny from renal progenitors is largely mysterious. Initial patterning of zebrafish renal progenitors in the intermediate mesoderm (IM) involves the formation of rostral and caudal domains, the former being reliant on retinoic acid (RA) signaling, and the latter being repressed by elevated RA levels. Here, using expression profiling to gain new insights into nephrogenesis, we discovered that the gene single minded family bHLH transcription factor 1a (sim1a) is dynamically expressed in the renal progenitors-first marking the caudal domain, then becoming restricted to the proximal segments, and finally exhibiting specific CS expression. In loss of function studies, sim1a knockdown expanded the PCT and abrogated both the PST and CS populations. Conversely, overexpression of sim1a modestly expanded the PST and CS, while it reduced the PCT. These results show that sim1a activity is necessary and partially sufficient to induce PST and CS fates, and suggest that sim1a may inhibit PCT fate and/or negotiate the PCT/PST boundary. Interestingly, the sim1a expression domain in renal progenitors is responsive to altered levels of RA, suggesting that RA regulates sim1a, directly or indirectly, during nephrogenesis. sim1a deficient embryos treated with exogenous RA formed nephrons that were predominantly composed of PCT segments, but lacked the enlarged PST observed in RA treated wild-types, indicating that RA is not sufficient to rescue the PST in the absence of sim1a expression. Alternately, when sim1a knockdowns were exposed to the RA inhibitor diethylaminobenzaldehyde (DEAB), the CS was abrogated rather than expanded as seen in DEAB treated wild-types, revealing that CS formation in the absence of sim1a cannot be rescued by RA biosynthesis abrogation. Taken together, these data reveal previously unappreciated roles for sim1a in zebrafish pronephric proximal tubule and CS patterning, and are consistent with the model that sim1a acts downstream of RA to mitigate the formation of these lineages. These findings provide new insights into the genetic pathways that direct nephron development, and may have implications for understanding renal birth defects and kidney reprogramming. (C) 2014 The Authors. Published by Elsevier Inc.