HNF1β Is Essential for Nephron Segmentation during Nephrogenesis
HNF1β Is Essential for Nephron Segmentation during Nephrogenesis
复制标题
DOI：
10.1681/asn.2012070756
复制
发表时间：
2013-01-01
影响因子：
13.6
通讯作者：
Davidson, Alan J.
中科院分区：
文献类型：
--
作者：
Naylor, Richard W.;Przepiorski, Aneta;Davidson, Alan J.
肾单位包括血液过滤器和上皮小管，上皮小管被细分为近端和远端段，但在肾器官发生期间指导这种模式的是什么还不清楚。使用斑马鱼，我们发现，HNF 1 β旁系同源hnf 1ba和hnf 1bb，编码同源结构域转录因子，是必要的肾单位的正常分割。缺乏hnf 1ba和hnf 1bb的胚胎不表达近端和远端节标记，但仍发育成上皮小管。启动hnf 1ba/B的表达需要Pax 2a和Pax 8，但hnf 1ba/b缺陷的胚胎并没有表现出预期的下调pax 2a和pax 8在发育后期，这表明复杂的调控回路涉及这些分子。hnf 1ba/B缺陷的胚胎也不表达irx 3 B转录因子，该因子负责第一远端小管节段的分化。相反，irx 3 B缺陷的胚胎表现出hnf 1 ba/B转录在远端早期段下调，这表明一个特定的节段调控电路。缺乏hnf 1 ba/B也导致足细胞异位扩张到近端小管区域。上位性实验表明足细胞的形成需要wt 1a和rbpj，wt 1a编码Wilms肿瘤抑制因子-1转录因子，rbpj编码经典Notch信号传导的介质，位于hnf 1ba/B的下游或平行。两者合计，这些结果表明，Hnf 1 β因子是必不可少的正常分割的肾单位在肾器官发生。J Am Soc Nephrol 24：77-87，2013. doi：10.1681/ASN.2012070756
Nephrons comprise a blood filter and an epithelial tubule that is subdivided into proximal and distal segments, but what directs this patterning during kidney organogenesis is not well understood. Using zebrafish, we found that the HNF1 beta paralogues hnf1ba and hnf1bb, which encode homeodomain transcription factors, are essential for normal segmentation of nephrons. Embryos deficient in hnf1ba and hnf1bb did not express proximal and distal segment markers, yet still developed an epithelial tubule. Initiating hnf1ba/b expression required Pax 2a and Pax8, but hnf1ba/b-deficient embryos did not exhibit the expected downregulation of pax2a and pax8 at later stages of development, suggesting complex regulatory loops involving these molecules. Embryos deficient in hnf1ba/b also did not express the irx3b transcription factor, which is responsible for differentiation of the first distal tubule segment. Reciprocally, embryos deficient in irx3b exhibited downregulation of hnf1ba/b transcripts in the distal early segment, suggesting a segment-specific regulatory circuit. Deficiency of hnf1ba/b also led to ectopic expansion of podocytes into the proximal tubule domain. Epistasis experiments showed that the formation of podocytes required wt1a, which encodes the Wilms' tumor suppressor-1 transcription factor, and rbpj, which encodes a mediator of canonical Notch signaling, downstream or parallel to hnf1ba/b. Taken together, these results suggest that Hnf1 beta factors are essential for normal segmentation of nephrons during kidney organogenesis. J Am Soc Nephrol 24: 77-87, 2013. doi: 10.1681/ASN.2012070756