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.

尿道发育不全，包括输尿管闭合失败，是人类遗传性疾病中常见的表型之一，其机制尚不清楚。因此，本研究旨在研究整个小鼠尿道发育过程中LIM同源框转录因子Isl1的表达，功能和相关机制。结果表明，Isl1在生殖器结节（GT）的尿道上皮细胞和间充质细胞中高表达。功能性研究，利用他莫昔芬诱导进行ISL1敲除小鼠模型。组织学和形态学结果表明，Isl1缺失引起尿道发育不全并抑制复杂的尿道上皮成熟。此外，我们显示，Isl1缺失的小鼠未能维持肾小管形态发生过程中更新尿道上皮所需的祖细胞群，并显示出尿道内细胞死亡显着增加。双重荧光素酶报告基因检测和酵母一杂交检测表明，ISL1通过直接靶向Shh基因对于正常尿道发育必不可少。总体而言，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。