Grassmeyer Justin, Mukherjee Malini, deRiso Jennifer, Hettinger Casey, Bailey Monica, Sinha Satrajit, Visvader Jane E, Zhao Haotian, Fogarty Eric, Surendran Kameswaran
Sanford Children's Health Research Center, Sanford Research, 2301 East 60(th) Street North, Sioux Falls, SD 57104, USA.
Augustana University, Sioux Falls, SD, USA.
Dev Biol. 2017 Apr 1;424(1):77-89. doi: 10.1016/j.ydbio.2017.02.007. Epub 2017 Feb 17.
The mammalian kidney collecting ducts are critical for water, electrolyte and acid-base homeostasis and develop as a branched network of tubular structures composed of principal cells intermingled with intercalated cells. The intermingled nature of the different collecting duct cell types has made it challenging to identify unique and critical factors that mark and/or regulate the development of the different collecting duct cell lineages. Here we report that the canonical Notch signaling pathway components, RBPJ and Presinilin1 and 2, are involved in patterning the mouse collecting duct cell fates by maintaining a balance between principal cell and intercalated cell fates. The relatively reduced number of principal cells in Notch-signaling-deficient kidneys offered a unique genetic leverage to identify critical principal cell-enriched factors by transcriptional profiling. Elf5, which codes for an ETS transcription factor, is one such gene that is down-regulated in kidneys with Notch-signaling-deficient collecting ducts. Additionally, Elf5 is among the earliest genes up regulated by ectopic expression of activated Notch1 in the developing collecting ducts. In the kidney, Elf5 is first expressed early within developing collecting ducts and remains on in mature principal cells. Lineage tracing of Elf5-expressing cells revealed that they are committed to the principal cell lineage by as early as E16.5. Over-expression of ETS Class IIa transcription factors, including Elf5, Elf3 and Ehf, increase the transcriptional activity of the proximal promoters of Aqp2 and Avpr2 in cultured ureteric duct cell lines. Conditional inactivation of Elf5 in the developing collecting ducts results in a small but significant reduction in the expression levels of Aqp2 and Avpr2 genes. We have identified Elf5 as an early maker of the principal cell lineage that contributes to the expression of principal cell specific genes.
哺乳动物的肾集合管对于水、电解质和酸碱平衡至关重要，它发育为一个由主细胞和闰细胞相互交织组成的分支管状结构网络。不同集合管细胞类型相互交织的特性使得识别标记和/或调节不同集合管细胞谱系发育的独特关键因子具有挑战性。在此，我们报告经典的Notch信号通路成分RBPJ以及早老素1和2参与了小鼠集合管细胞命运的模式形成，通过维持主细胞和闰细胞命运之间的平衡来实现。Notch信号缺陷型肾脏中主细胞数量相对减少，这为通过转录谱分析鉴定关键的富含主细胞的因子提供了独特的遗传优势。Elf5编码一种ETS转录因子，它是在Notch信号缺陷型集合管的肾脏中表达下调的此类基因之一。此外，Elf5是发育中的集合管中活化Notch1异位表达最早上调的基因之一。在肾脏中，Elf5最早在发育中的集合管早期表达，并在成熟的主细胞中持续表达。对表达Elf5的细胞进行谱系追踪表明，它们早在胚胎第16.5天就已确定为主细胞谱系。包括Elf5、Elf3和Ehf在内的ETS IIa类转录因子的过表达增加了培养的输尿管导管细胞系中Aqp2和Avpr2近端启动子的转录活性。在发育中的集合管中条件性失活Elf5会导致Aqp2和Avpr2基因的表达水平出现小幅但显著的降低。我们已将Elf5鉴定为主细胞谱系的早期标志物，它有助于主细胞特异性基因的表达。
