Niswander L, Jeffrey S, Martin G R, Tickle C
Department of Anatomy, School of Medicine, University of California at San Francisco 94143-0452.
Nature. 1994 Oct 13;371(6498):609-12. doi: 10.1038/371609a0.
Limb development depends on signals from the apical ectodermal ridge and underlying mesenchyme. Fibroblast growth factor (FGF) can replace the ridge and, because Fgf4 RNA is localized to the mouse posterior ridge, we proposed that FGF4 is the endogenous ridge signal. Ridge signals control limb outgrowth and maintain the zone of polarizing activity (ZPA) at the limb posterior margin, which is important in limb pattering: a ZPA graft to limb anterior mesenchyme causes cell respecification and mirror-image duplications. Sonic hedgehog (SHH) has polarizing activity, and Shh RNA co-localizes with ZPA activity, suggesting SHH is the endogenous polarizing signal. We have investigated the molecular regulation of Fgf4 and Shh expression. We report here that Fgf4 expression in the ridge can be regulated by Shh-expressing cells. Moreover, Shh expression in mesenchyme can be activated by FGF4 in combination with retinoic acid. Once induced, Shh expression can be maintained by FGF4 alone, thus establishing a positive feedback loop between ZPA and ridge.
肢体发育依赖于来自顶端外胚层嵴和其下方间充质的信号。成纤维细胞生长因子（FGF）可替代嵴，并且由于Fgf4 RNA定位于小鼠后嵴，我们提出FGF4是内源性嵴信号。嵴信号控制肢体生长并维持肢体后缘的极化活性区（ZPA），这在肢体模式形成中很重要：将ZPA移植到肢体前间充质会导致细胞重新编程和镜像重复。音猬因子（SHH）具有极化活性，并且Shh RNA与ZPA活性共定位，表明SHH是内源性极化信号。我们研究了Fgf4和Shh表达的分子调控。我们在此报告，嵴中Fgf4的表达可由表达Shh的细胞调节。此外，间充质中Shh的表达可由FGF4与视黄酸联合激活。一旦被诱导，Shh的表达可仅由FGF4维持，从而在ZPA和嵴之间建立正反馈回路。
