Abstract：
The Wolffian ducts (WD) are paired epithelial tubules central to the development of the mammalian genitourinary tract. Outgrowths from the WD known as the ureteric buds (UB) generate the collecting ducts of the kidney. Later during development, the caudal portion of the WD will form the vas deferens, epididymis and seminal vesicle in males, and will degenerate in females. While the genetic pathways controlling the development of the UB are firmly established, less is known about those governing development of WD portions caudal to the UB. Sprouty proteins are inhibitors of receptor tyrosine kinase (RTK) signaling in vivo. We have recently shown that homozygous mutation of a conserved tyrosine (Tyr53) of Spry1 results in UB defects indistinguishable from that of Spry1 null mice. Here, we show that heterozygosity for the Spry1 Y53A allele causes caudal WD developmental defects consisting of ectopically branched seminal vesicles in males and persistent WD in females, without affecting kidney development. Detailed analysis reveals that this phenotype also occurs in Spry1+/- mice but with a much lower penetrance, indicating that removal of tyrosine 53 generates a dominant negative mutation in vivo. Supporting this notion, concomitant deletion of one allele of Spry1 and Spry2 also recapitulates the genital phenotype of Spry1Y53A/+ mice with high penetrance. Mechanistically, we show that unlike the effects of Spry1 in kidney development, these caudal WD defects are independent of Ret signaling, but can be completely rescued by lowering the genetic dosage of Fgf10. In conclusion, mutation of tyrosine 53 of Spry1 generates a dominant negative allele that uncovers fine-tuning of caudal WD development by Sprouty genes.
摘要：
Wolffian导管（WD）是成对的上皮小管，是哺乳动物泌尿生殖道发育的中心。被称为输尿管芽（UB）的WD的外生物产生肾脏的集合管。在开发过程中，WD的尾部将形成输精管，男性的附睾和精囊，会在女性身上退化。虽然控制UB发育的遗传途径已经确立，关于控制WD尾端到UB的部分发展的人知之甚少。Sprouty蛋白是体内受体酪氨酸激酶（RTK）信号传导的抑制剂。我们最近表明，Spry1的保守酪氨酸（Tyr53）的纯合突变会导致UB缺陷，与Spry1空小鼠的UB缺陷无法区分。这里,我们表明，Spry1Y53A等位基因的杂合性导致尾端WD发育缺陷，包括男性的异位分支精囊和女性的持续性WD，不影响肾脏发育。详细分析表明，这种表型也发生在Spry1+/-小鼠中，但外显率低得多，表明酪氨酸53的去除在体内产生显性负突变。支持这个概念，Spry1和Spry2的一个等位基因的同时缺失也概括了具有高外显率的Spry1Y53A/小鼠的生殖器表型。机械上,我们发现与Spry1对肾脏发育的影响不同，这些尾端WD缺陷与Ret信号无关，但可以通过降低Fgf10的遗传剂量来完全挽救。总之,Spry1的酪氨酸53突变产生显性阴性等位基因，该等位基因揭示了Sprouty基因对尾端WD发育的微调。
