Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
J Am Soc Nephrol. 2013 Jul;24(8):1242-9. doi: 10.1681/ASN.2012050528. Epub 2013 May 2.
Islet1 (Isl1) is a transcription factor transiently expressed in a subset of heart and limb progenitors. During studies of limb development, conditional Isl1 deletion produced unexpected kidney abnormalities. Here, we studied the renal expression of Isl1 and whether it has a role in kidney development. In situ hybridization revealed Isl1 expression in the mesenchymal cells surrounding the base of the ureteric bud in mice. Conditional deletion of Isl1 caused kidney agenesis or hypoplasia and hydroureter, a phenotype resembling human congenital anomalies of the kidney and urinary tract (CAKUT). The absence of Isl1 led to ectopic branching of the ureteric bud out from the nephric duct or to the formation of accessory buds, both of which could lead to obstruction of the ureter-bladder junction and consequent hydroureter. The abnormal elongation and poor branching of the ureteric buds were the likely causes of the kidney agenesis or hypoplasia. Furthermore, the lack of Isl1 reduced the expression of Bmp4, a gene implicated in the CAKUT-like phenotype, in the metanephric region before ureteric budding. In conclusion, Isl1 is essential for proper development of the kidney and ureter by repressing the aberrant formation of the ureteric bud. These observations call for further studies to investigate whether Isl1 may be a causative gene for human CAKUT.
胰岛 1 转录因子（Islet1，Isl1）在心脏和肢体祖细胞的亚群中短暂表达。在肢体发育研究中，条件性 Isl1 缺失产生了意想不到的肾脏异常。在这里，我们研究了 Isl1 在肾脏中的表达及其在肾脏发育中的作用。原位杂交显示，Isl1 在小鼠输尿管芽基部周围的间充质细胞中表达。条件性缺失 Isl1 导致肾脏发育不全或发育不良以及输尿管积水，这一表型类似于人类先天性肾和尿路异常（CAKUT）。Isl1 的缺失导致输尿管芽从肾管异常分支或形成附属芽，这两者都可能导致输尿管-膀胱交界处阻塞，进而导致输尿管积水。输尿管芽异常伸长和分支不良可能是肾脏发育不全或发育不良的原因。此外，Isl1 的缺乏减少了 Bmp4 的表达，Bmp4 是一个与 CAKUT 样表型相关的基因，在输尿管芽形成前的后肾区。总之，Isl1 通过抑制输尿管芽的异常形成，对肾脏和输尿管的正常发育至关重要。这些观察结果呼吁进一步研究，以探讨 Isl1 是否可能是人类 CAKUT 的致病基因。
