Bohnenpoll Tobias, Wittern Anna B, Mamo Tamrat M, Weiss Anna-Carina, Rudat Carsten, Kleppa Marc-Jens, Schuster-Gossler Karin, Wojahn Irina, Lüdtke Timo H-W, Trowe Mark-Oliver, Kispert Andreas
Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.
PLoS Genet. 2017 Aug 10;13(8):e1006951. doi: 10.1371/journal.pgen.1006951. eCollection 2017 Aug.
The differentiated cell types of the epithelial and mesenchymal tissue compartments of the mature ureter of the mouse arise in a precise temporal and spatial sequence from uncommitted precursor cells of the distal ureteric bud epithelium and its surrounding mesenchyme. Previous genetic efforts identified a member of the Hedgehog (HH) family of secreted proteins, Sonic hedgehog (SHH) as a crucial epithelial signal for growth and differentiation of the ureteric mesenchyme. Here, we used conditional loss- and gain-of-function experiments of the unique HH signal transducer Smoothened (SMO) to further characterize the cellular functions and unravel the effector genes of HH signaling in ureter development. We showed that HH signaling is not only required for proliferation and SMC differentiation of cells of the inner mesenchymal region but also for survival of cells of the outer mesenchymal region, and for epithelial proliferation and differentiation. We identified the Forkhead transcription factor gene Foxf1 as a target of HH signaling in the ureteric mesenchyme. Expression of a repressor version of FOXF1 in this tissue completely recapitulated the mesenchymal and epithelial proliferation and differentiation defects associated with loss of HH signaling while re-expression of a wildtype version of FOXF1 in the inner mesenchymal layer restored these cellular programs when HH signaling was inhibited. We further showed that expression of Bmp4 in the ureteric mesenchyme depends on HH signaling and Foxf1, and that exogenous BMP4 rescued cell proliferation and epithelial differentiation in ureters with abrogated HH signaling or FOXF1 function. We conclude that SHH uses a FOXF1-BMP4 module to coordinate the cellular programs for ureter elongation and differentiation, and suggest that deregulation of this signaling axis occurs in human congenital anomalies of the kidney and urinary tract (CAKUT).
小鼠成熟输尿管上皮和间充质组织区室的分化细胞类型，从输尿管芽远端上皮及其周围间充质的未定向前体细胞，以精确的时间和空间顺序产生。先前的遗传学研究确定了分泌蛋白刺猬（HH）家族的一个成员，即音猬因子（SHH），是输尿管间充质生长和分化的关键上皮信号。在这里，我们利用独特的HH信号转导蛋白平滑肌瘤（SMO）的条件性功能缺失和功能获得实验，进一步表征细胞功能，并揭示HH信号在输尿管发育中的效应基因。我们表明，HH信号不仅是内间充质区域细胞增殖和SMC分化所必需的，也是外间充质区域细胞存活以及上皮增殖和分化所必需的。我们确定叉头转录因子基因Foxf1是输尿管间充质中HH信号的一个靶点。在该组织中表达FOXF1的阻遏物版本，完全重现了与HH信号缺失相关的间充质和上皮增殖及分化缺陷，而当HH信号被抑制时，在内间充质层重新表达野生型版本的FOXF1可恢复这些细胞程序。我们进一步表明，输尿管间充质中Bmp4的表达依赖于HH信号和Foxf1，并且外源性BMP4可挽救HH信号或FOXF1功能缺失的输尿管中的细胞增殖和上皮分化。我们得出结论，SHH利用FOXF1 - BMP4模块来协调输尿管伸长和分化的细胞程序，并表明该信号轴的失调发生在人类先天性肾脏和尿路异常（CAKUT）中。
