Poureetezadi Shahram Jevin, Cheng Christina N, Chambers Joseph M, Drummond Bridgette E, Wingert Rebecca A
Department of Biological Sciences, University of Notre Dame, Notre Dame, United States.
Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, United States.
Elife. 2016 Dec 20;5:e17551. doi: 10.7554/eLife.17551.
Kidney formation involves patterning events that induce renal progenitors to form nephrons with an intricate composition of multiple segments. Here, we performed a chemical genetic screen using zebrafish and discovered that prostaglandins, lipid mediators involved in many physiological functions, influenced pronephros segmentation. Modulating levels of prostaglandin E2 (PGE) or PGB restricted distal segment formation and expanded a proximal segment lineage. Perturbation of prostaglandin synthesis by manipulating Cox1 or Cox2 activity altered distal segment formation and was rescued by exogenous PGE. Disruption of the PGE receptors Ptger2a and Ptger4a similarly affected the distal segments. Further, changes in Cox activity or PGE levels affected expression of the transcription factors and that mitigate pronephros segment patterning. These findings show for the first time that PGE is a regulator of nephron formation in the zebrafish embryonic kidney, thus revealing that prostaglandin signaling may have implications for renal birth defects and other diseases.
肾脏形成涉及模式化事件，这些事件诱导肾祖细胞形成具有多个节段复杂组成的肾单位。在此，我们利用斑马鱼进行了化学遗传学筛选，发现前列腺素（参与多种生理功能的脂质介质）影响前肾节段化。调节前列腺素E2（PGE）或PGB的水平会限制远端节段的形成并扩展近端节段谱系。通过操纵Cox1或Cox2活性来干扰前列腺素合成会改变远端节段的形成，而外源性PGE可使其恢复。PGE受体Ptger2a和Ptger4a的破坏同样会影响远端节段。此外，Cox活性或PGE水平的变化会影响转录因子的表达，这些转录因子可减轻前肾节段模式化。这些发现首次表明PGE是斑马鱼胚胎肾脏中肾单位形成的调节因子，从而揭示前列腺素信号传导可能与肾脏出生缺陷及其他疾病有关。
