Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA.
J Am Soc Nephrol. 2012 Apr;23(4):641-51. doi: 10.1681/ASN.2011080829. Epub 2012 Jan 26.
Intraflagellar transport (IFT) complexes A and B build and maintain primary cilia. In the mouse, kidney-specific or hypomorphic mutant alleles of IFT complex B genes cause polycystic kidneys, but the influence of IFT complex A proteins on renal development is not well understood. In the present study, we found that HoxB7-Cre-driven deletion of the complex A gene Ift140 from collecting ducts disrupted, but did not completely prevent, cilia assembly. Mutant kidneys developed collecting duct cysts by postnatal day 5, with rapid cystic expansion and renal dysfunction by day 15 and little remaining parenchymal tissue by day 20. In contrast to many models of polycystic kidney disease, precystic Ift140-deleted collecting ducts showed normal centrosomal positioning and no misorientation of the mitotic spindle axis, suggesting that disruption of oriented cell division is not a prerequisite to cyst formation in these kidneys. Precystic collecting ducts had an increased mitotic index, suggesting that cell proliferation may drive cyst expansion even with normal orientation of the mitotic spindle. In addition, we observed significant increases in expression of canonical Wnt pathway genes and mediators of Hedgehog and tissue fibrosis in highly cystic, but not precystic, kidneys. Taken together, these studies indicate that loss of Ift140 causes pronounced renal cystic disease and suggest that abnormalities in several different pathways may influence cyst progression.
纤毛内运输 (IFT) 复合物 A 和 B 构建和维持初级纤毛。在小鼠中，IFT 复合物 B 基因的肾脏特异性或低功能突变等位基因导致多囊肾，但 IFT 复合物 A 蛋白对肾脏发育的影响尚不清楚。在本研究中，我们发现 HoxB7-Cre 驱动的集合管中 Ift140 复合物 A 基因的缺失破坏了纤毛组装，但并没有完全阻止其组装。突变肾脏在出生后第 5 天发展为集合管囊肿，在第 15 天迅速扩张并出现肾功能障碍，在第 20 天几乎没有剩余的实质组织。与许多多囊肾病模型不同，未发生囊肿的 Ift140 缺失集合管显示中心体定位正常，有丝分裂纺锤体轴没有错位，这表明在这些肾脏中，定向细胞分裂的破坏不是囊肿形成的先决条件。未发生囊肿的集合管有丝分裂指数增加，表明即使有丝分裂纺锤体的定向正常，细胞增殖也可能导致囊肿扩张。此外，我们还观察到高度囊肿化但未发生囊肿的肾脏中经典 Wnt 途径基因和 Hedgehog 及组织纤维化的调节剂表达显著增加。总之，这些研究表明 Ift140 的缺失导致明显的肾脏囊性疾病，并表明几种不同途径的异常可能影响囊肿的进展。
