Tfap2a is a novel gatekeeper of nephron differentiation during kidney development
Tfap2a is a novel gatekeeper of nephron differentiation during kidney development
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DOI：
10.1242/dev.172387
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发表时间：
2019-07-01
期刊：
影响因子：
4.6
通讯作者：
Wingert, Rebecca A.
中科院分区：
文献类型：
--
作者：
Chambers, Brooke E.;Gerlach, Gary F.;Wingert, Rebecca A.
被称为肾单位的肾脏功能单位在发育过程中经历模式化事件，形成具有离散生理特性的分段细胞区室阵列。在这里，通过使用斑马鱼的正向遗传筛选，我们报告了转录因子 AP-2 α (tfap2a) 协调基因调控网络的发现，该网络激活前肾远端节段的终末分化程序。我们发现 tfap2a 作用于易洛魁同源框 3b (irx3b)（一种远端谱系转录因子）的下游，以操作由 tfap2b、irx1a 和编码溶质转运蛋白的基因组成的回路，这些基因决定远端肾单位片段的专门代谢功能。有趣的是，这个调节节点不同于其他分化检查点，例如极性建立和纤毛发生。因此，我们的研究揭示了对分化的遗传控制的见解，其中tfap2a对于调节斑马鱼原发个体发育最后一层的一系列片段转运蛋白特征至关重要。这些发现对于理解肾脏出生缺陷以及在体内重现肾发生以促进药物发现和再生疗法的努力具有相关性。
Renal functional units known as nephrons undergo patterning events during development that create a segmental array of cellular compartments with discrete physiological identities. Here, from a forward genetic screen using zebrafish, we report the discovery that transcription factor AP-2 alpha (tfap2a) coordinates a gene regulatory network that activates the terminal differentiation program of distal segments in the pronephros. We found that tfap2a acts downstream of Iroquois homeobox 3b (irx3b), a distal lineage transcription factor, to operate a circuit consisting of tfap2b, irx1a and genes encoding solute transporters that dictate the specialized metabolic functions of distal nephron segments. Interestingly, this regulatory node is distinct from other checkpoints of differentiation, such as polarity establishment and ciliogenesis. Thus, our studies reveal insights into the genetic control of differentiation, where tfap2a is essential for regulating a suite of segment transporter traits at the final tier of zebrafish pronephros ontogeny. These findings have relevance for understanding renal birth defects, as well as efforts to recapitulate nephrogenesis in vivo to facilitate drug discovery and regenerative therapies.