Congenital anomalies of external genitalia affect approximately 1 in 125 live male births. Development of the genital tubercle, the precursor of the penis and clitoris, is regulated by the urethral plate epithelium, an endodermal signaling center. Signaling activity of the urethral plate is mediated by Sonic hedgehog (SHH), which coordinates outgrowth and patterning of the genital tubercle by controlling cell cycle kinetics and expression of downstream genes. The mechanisms that govern Shh transcription in urethral plate cells are largely unknown. Here we show that deletion of Foxa1 and Foxa2 results in persistent cloaca, an incomplete separation of urinary, genital, and anorectal tracts, and severe hypospadias, a failure of urethral tubulogenesis. Loss of Foxa2 and only one copy of Foxa1 results in urethral fistula, an additional opening of the penile urethra. Foxa1/a2 participate in an autoregulatory feedback loop with Shh, in which FOXA1 and FOXA2 positively regulate transcription of Shh in the urethra, and SHH feeds back to negatively regulate Foxa1 and Foxa2 expression. These findings reveal novel roles for Foxa genes in development of the urethral tube and in division of the embryonic cloaca.

外生殖器的先天性异常影响大约125个活着的男婴中的1个。生殖器结节（阴茎和阴蒂的前体）的发育受尿道板上皮（内胚层信号传递中心）调节。声波刺猬（SHH）介导了尿道板的信号传导活性，该信号通过控制细胞周期动力学和下游基因的表达来协调生殖器官结节的生长和模式。在尿道板细胞中控制Shh转录的机制在很大程度上尚不清楚。在这里，我们显示Foxa1和Foxa2的删除会导致持续的泄殖腔，泌尿，生殖器和肛门直肠分离不完全，以及严重的尿道下裂，尿道微管生成失败。的损失Foxa2和Foxa1的一个副本只会导致尿道瘘，这是阴茎尿道的另一个开口。Foxa1 / a2与Shh参与自调节反馈回路，其中FOXA1和FOXA2在尿道中正向调节Shh的转录，而SHH反馈负向调节Foxa1和Foxa2的表达。这些发现揭示了Foxa基因在尿道管发育和泄殖腔分裂中的新作用。