Esrrg functions in early branch generation of the ureteric bud and is essential for normal development of the renal papilla

被引:25
作者
Berry, Rachel [1 ]
Harewood, Louise [1 ]
Pei, Liming [2 ]
Fisher, Malcolm [1 ]
Brownstein, David [3 ]
Ross, Allyson [1 ]
Alaynick, William A. [2 ]
Moss, Julie [1 ]
Hastie, Nicholas D. [1 ]
Hohenstein, Peter [1 ]
Davies, Jamie A. [4 ]
Evans, Ronald M. [2 ]
FitzPatrick, David R. [1 ]
机构
[1] Western Gen Hosp, MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland
[2] Howard Hughes Med Inst, Salk Inst, La Jolla, CA 92037 USA
[3] Univ Edinburgh, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland
[4] Univ Edinburgh, Ctr Integrat Physiol, Edinburgh, Midlothian, Scotland
基金
英国医学研究理事会;
关键词
ERR-GAMMA; IDENTIFICATION; DIFFERENTIATION; DYSPLASIA; LIGAND; GENE; RAT;
D O I
10.1093/hmg/ddq530
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Congenital anomalies of the kidney and urinary tract (CAKUTs) are common disorders of human development affecting the renal parechyma, renal pelvis, ureter, bladder and urethra; they show evidence of shared genetic aetiology, although the molecular basis of this remains unknown in the majority of cases. Breakpoint mapping of a de novo, apparently balanced, reciprocal translocation associated with bilateral renal agenesis has implicated the gene encoding the nuclear steroid hormone receptor ESRRG as a candidate gene for CAKUT. Here we show that the Esrrg protein is detected throughout early ureteric ducts as cytoplasmic/sub-membranous staining; with nuclear localization seen in developing nephrons. In 14.5-16.5 dpc (days post-conception) mouse embryos, Esrrg localizes to the subset of ductal tissue within the kidney, liver and lung. The renal ductal expression becomes localized to renal papilla by 18.5 dpc. Perturbation of function was performed in embryonic mouse kidney culture using pooled siRNA to induce knock-down and a specific small-molecule agonist to induce aberrant activation of Esrrg. Both resulted in severe abnormality of early branching events of the ureteric duct. Mouse embryos with a targeted inactivation of Esrrg on both alleles (Esrrg(-/-)) showed agenesis of the renal papilla but normal development of the cortex and remaining medulla. Taken together, these results suggest that Esrrg is required for early branching events of the ureteric duct that occur prior to the onset of nephrogenesis. These findings confirm ESRRG as a strong candidate gene for CAKUT.
引用
收藏
页码:917 / 926
页数:10
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