Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Dev Dyn. 2011 Aug;240(8):2011-27. doi: 10.1002/dvdy.22691.
Kidney nephrons are composed of proximal and distal tubule segments that perform unique roles in excretion. The developmental pathways that establish nephron segment identities from renal progenitors are poorly understood. Here, we used the zebrafish pronephros to study nephron segmentation. We found that zebrafish nephron progenitors undergo elaborate spatiotemporal expression changes of many genes before adopting a segment fate. Initially, two domains of nephron progenitors are established, then are subdivided and demarcate individual nephron segments. Using genetic and chemical genetic models of retinoic acid (RA) deficiency, we discovered that RA modulates rostral progenitor formation. To delineate downstream pathways, we knocked down the irx3b transcription factor and found it regulates proximal tubule segment size and distal segment differentiation. Our results suggest a model whereby RA patterns the early field of nephron progenitors, with subsequent factors like irx3b acting to refine later progenitor subdomains and ensure activation of segment-specific gene programs.
肾单位由近端和远端小管段组成，它们在排泄中发挥独特的作用。肾脏祖细胞中建立肾单位节段特征的发育途径尚不清楚。在这里，我们使用斑马鱼的前肾来研究肾单位的分段。我们发现，斑马鱼肾单位祖细胞在采用节段命运之前经历了许多基因的精细时空表达变化。最初，两个肾单位祖细胞域建立，然后细分并划定单个肾单位段。使用维甲酸 (RA) 缺乏的遗传和化学遗传模型，我们发现 RA 调节颅侧祖细胞的形成。为了描绘下游途径，我们敲低了 irx3b 转录因子，发现它调节近端小管段的大小和远端段的分化。我们的结果表明，RA 模式化了肾单位祖细胞的早期场，随后的因子（如 irx3b）作用于细化后期祖细胞亚域，并确保激活特定节段的基因程序。
