LIM homeodomain transcription factor Isl1 affects urethral epithelium differentiation and apoptosis via Shh
LIM homeodomain transcription factor Isl1 affects urethral epithelium differentiation and apoptosis via Shh
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LIM同源域转录因子Isl1通过Shh影响尿道上皮分化和凋亡
DOI：
10.1038/s41419-019-1952-z
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发表时间：
2019-09-26
影响因子：
9
通讯作者：
Cui, Sheng
中科院分区：
文献类型：
--
作者：
Su, Tiantian;Liu, Hui;Cui, Sheng
尿道发育不全，包括尿道管闭合失败，是人类遗传性疾病中观察到的常见表型之一，其机制尚不清楚。因此，本研究旨在研究LIM同源盒转录因子Isl 1在小鼠尿道发育过程中的表达、功能及其相关机制。结果显示，Isl1在尿道上皮细胞和生殖结节间充质细胞中高表达。通过利用他莫昔芬诱导的Isl1基因敲除小鼠模型进行功能研究。组织学和形态学结果表明，Isl1基因缺失导致尿道发育不全，抑制了复合尿道上皮的成熟。此外，我们发现，Isl1基因缺失的小鼠未能维持所需的祖细胞群体的尿道上皮更新在管状形态发生和尿道内表现出显着增加的细胞死亡。双荧光素酶报告基因测定和酵母单杂交测定表明，ISL 1通过直接靶向Shh基因对正常尿道发育至关重要。总的来说，这里提出的结果表明，Isl1在小鼠尿道发育中起着至关重要的作用，从而增加了我们了解遗传性尿道发育不全的机制基础的潜力。
Urethral hypoplasia, including failure of urethral tube closure, is one of the common phenotypes observed in hereditary human disorders, the mechanism of which remains unclear. The present study was thus designed to study the expression, functions, and related mechanisms of the LIM homeobox transcription factor Isl1 throughout mouse urethral development. Results showed that Isl1 was highly expressed in urethral epithelial cells and mesenchymal cells of the genital tubercle (GT). Functional studies were carried out by utilizing the tamoxifen-inducible Isl1-knockout mouse model. Histological and morphological results indicated that Isl1 deletion caused urethral hypoplasia and inhibited maturation of the complex urethral epithelium. In addition, we show that Isl1-deleted mice failed to maintain the progenitor cell population required for renewal of urethral epithelium during tubular morphogenesis and exhibited significantly increased cell death within the urethra. Dual-Luciferase reporter assays and yeast one-hybrid assays showed that ISL1 was essential for normal urethral development by directly targeting the Shh gene. Collectively, results presented here demonstrated that Isl1 plays a crucial role in mouse urethral development, thus increasing our potential for understanding the mechanistic basis of hereditary urethral hypoplasia.