Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux.
Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux.
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DOI：
10.1371/journal.pone.0056062
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bates CM
中科院分区：
文献类型：
--
作者：
Walker KA;Sims-Lucas S;Di Giovanni VE;Schaefer C;Sunseri WM;Novitskaya T;de Caestecker MP;Chen F;Bates CM
Pax3cre 介导的肾和泌尿道间充质中广泛的成纤维细胞生长因子受体 2 (Fgfr2) 缺失导致输尿管芽 (UB) 诱导缺陷和膀胱输尿管反流 (VUR)，但其机制尚不清楚。在这里，我们研究了 Fgfr2 是否在狼管周围基质 (ST) 中特异性作用来调节 UB 诱导和 VUR 的发育以及 Fgfr2 活性的机制。我们使用 Tbx18cre 小鼠有条件地删除 ST (Fgfr2ST−/−) 中的 Fgfr2。为了寻找年轻胚胎中输尿管芽诱导缺陷，我们评估了肾总管（CND）的长度和凋亡。我们对胚胎和出生后小鼠的尿路进行了 3D 重建和组织学分析，并对出生后小鼠进行了膀胱造影以检测 VUR。我们在年轻胚胎中进行了原位杂交和实时 PCR 以确定 UB 诱导缺陷的机制。我们证实 Fgfr2 在 ST 中表达，并且在胚胎第 10.5 天 (E) 的 Fgfr2ST−/− 小鼠中，Fgfr2 在该组织中被有效删除。 E11.5 Fgfr2ST−/− 小鼠具有随机的 UB 诱导位点，其中约 1/3 位于沃尔夫管的过高处，1/3 位于沃尔夫管的过低处；然而，E12.5 突变 CND 中的细胞凋亡没有改变。虽然输尿管组织学正常，但 E15.5 Fgfr2ST−/− 小鼠表现出输尿管插入膀胱的位置不正确，与输尿管诱导缺陷一致。虽然输尿管和膀胱组织学表现正常，但与对照组相比，出生后第 1 天 (P) 突变体的 VUR 发生率较高（75% 与 3%，p = 0.001），偶尔还存在其他缺陷，包括肾发育不全和双链体系统。 P1 突变小鼠的输尿管膀胱插入部位不正确，并且与 VUR 相关的膀胱内隧道长度缩短。 E10.5 Fgfr2ST−/− 小鼠基质组织中的 Bmp4 mRNA 减少，表明输尿管诱导和 VUR 表型的潜在机制。 FGFR2 突变可能导致人类 VUR。
Pax3cre-mediated deletion of fibroblast growth factor receptor 2 (Fgfr2) broadly in renal and urinary tract mesenchyme led to ureteric bud (UB) induction defects and vesicoureteral reflux (VUR), although the mechanisms were unclear. Here, we investigated whether Fgfr2 acts specifically in peri-Wolffian duct stroma (ST) to regulate UB induction and development of VUR and the mechanisms of Fgfr2 activity. We conditionally deleted Fgfr2 in ST (Fgfr2ST−/−) using Tbx18cre mice. To look for ureteric bud induction defects in young embryos, we assessed length and apoptosis of common nephric ducts (CNDs). We performed 3D reconstructions and histological analyses of urinary tracts of embryos and postnatal mice and cystograms in postnatal mice to test for VUR. We performed in situ hybridization and real-time PCR in young embryos to determine mechanisms underlying UB induction defects. We confirmed that Fgfr2 is expressed in ST and that Fgfr2 was efficiently deleted in this tissue in Fgfr2ST−/− mice at embryonic day (E) 10.5. E11.5 Fgfr2ST−/− mice had randomized UB induction sites with approximately 1/3 arising too high and 1/3 too low from the Wolffian duct; however, apoptosis was unaltered in E12.5 mutant CNDs. While ureters were histologically normal, E15.5 Fgfr2ST−/− mice exhibit improper ureteral insertion sites into the bladder, consistent with the ureteric induction defects. While ureter and bladder histology appeared normal, postnatal day (P) 1 mutants had high rates of VUR versus controls (75% versus 3%, p = 0.001) and occasionally other defects including renal hypoplasia and duplex systems. P1 mutant mice also had improper ureteral bladder insertion sites and shortened intravesicular tunnel lengths that correlated with VUR. E10.5 Fgfr2ST−/− mice had decreases in Bmp4 mRNA in stromal tissues, suggesting a mechanism underlying the ureteric induction and VUR phenotypes. Mutations in FGFR2 could possibly cause VUR in humans.
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影响因子：
3.7
作者：
Walker KA;Sims-Lucas S;Caruana G;Cullen-McEwen L;Li J;Sarraj MA;Bertram JF;Stenvers KL
通讯作者：
Stenvers KL
影响因子：
2.5
作者：
Sims-Lucas, Sunder;Cusack, Brian;Baust, Jeffrey;Eswarakumar, Veraragavan P.;Masatoshi, Hagiwara;Takeuchi, Akihide;Bates, Carlton M.
通讯作者：
Bates, Carlton M.
影响因子：
2.7
作者：
Poladia, DP;Kish, K;Bates, CM
通讯作者：
Bates, CM
影响因子：
4.6
作者：
Hoffman, MP;Kidder, BL;Larsen, M
通讯作者：
Larsen, M
影响因子：
4.6
作者：
Yu, K;Xu, JS;Ornitz, DM
通讯作者：
Ornitz, DM