Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4
Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4
复制标题
DOI：
10.1242/dev.022442
复制
发表时间：
2008-10-01
期刊：
影响因子：
4.6
通讯作者：
Fasano, Laurent
中科院分区：
文献类型：
--
作者：
Caubit, Xavier;Lye, Claire M.;Fasano, Laurent
输尿管收缩推动胎儿尿液从肾脏进入膀胱。在这里，我们表明，小鼠输尿管平滑肌细胞（SMC）的前体表达转录因子teashirt 3（TSHZ 3），TSHZ 3无效突变小鼠先天性肾积水没有解剖梗阻。离体，自发性收缩发生在近段的野生型胚胎输尿管外植体Tshz 3突变输尿管缺席。在体内，在发生肾积水之前，突变近端输尿管未能表达收缩SMC标记物，而这些分子在对照组中被检测到。突变胚胎输尿管表达Shh和Bmp 4转录正常，Ptch 1和pSMAD 1/5/8在目标SM前体中适当表达，而平滑肌细胞分化的关键调节因子myocardin在Tshz 3无效输尿管中不表达。在野生型胚胎肾脏移植物中，外源性BMP 4上调Tshz 3和myocardin的表达。更有趣的是，在Tshz 3突变体的肾脏移植物中，外源性BMP 4没有改善Tshz 3表型。因此，Tshz 3是SHH和BMP 4下游近端输尿管SMC分化所必需的。此外，“功能性”尿路梗阻的Tshz 3突变小鼠模型类似于先天性肾盂输尿管连接部梗阻，这是一种常见的人类畸形，表明TSHZ或相关基因变异可能导致这种疾病。
Ureteric contractions propel foetal urine from the kidney to the urinary bladder. Here, we show that mouse ureteric smooth muscle cell (SMC) precursors express the transcription factor teashirt 3 (TSHZ3), and that Tshz3-null mutant mice have congenital hydronephrosis without anatomical obstruction. Ex vivo, the spontaneous contractions that occurred in proximal segments of wildtype embryonic ureter explants were absent in Tshz3 mutant ureters. In vivo, prior to the onset of hydronephrosis, mutant proximal ureters failed to express contractile SMC markers, whereas these molecules were detected in controls. Mutant embryonic ureters expressed Shh and Bmp4 transcripts as normal, with appropriate expression of Ptch1 and pSMAD1/5/8 in target SM precursors, whereas myocardin, a key regulator for SMC differentiation, was not expressed in Tshz3-null ureters. In wild-type embryonic renal tract explants, exogenous BMP4 upregulated Tshz3 and myocardin expression. More interestingly, in Tshz3 mutant renal tract explants, exogenous BMP4 did not improve the Tshz3 phenotype. Thus, Tshz3 is required for proximal ureteric SMC differentiation downstream of SHH and BMP4. Furthermore, the Tshz3 mutant mouse model of 'functional' urinary obstruction resembles congenital pelvi-ureteric junction obstruction, a common human malformation, suggesting that TSHZ, or related, gene variants may contribute to this disorder.