Abstract

LIMB development depends on signals from the apical ectodermal ridge and underlying mesenchyme^1,2. Fibroblast growth factor (FGF) can replace the ridge^3,4 and, because Fgf4RNA is localized to the mouse posterior ridge⁵, we proposed that FGF4 is the endogenous ridge signal³. Ridge signals control limb outgrowth and maintain the zone of polarizing activity (ZPA) at the limb posterior margin⁶, which is important in limb patterning: a ZPA graft to limb anterior mesenchyme causes cell respecification and mirror-image duplications^1,2. Sonic hedgehog (SHH^7,8) has polar-izing activity, and Shh RNA. co-localizes with ZPA activity, suggesting SHH is the endogenous polarizing signal⁷. We have investigated the molecular regulation of Fgf4 and Shh expression. We report here that Fgf4 expression in the ridge can be regulated byshh-expressing cells. Moreover, Shh expression in mesenchyme can be activated by FGF4 in combination with retinoic acid. Once induced, Shhexpression can be maintained by FGF4 alone, thus establishing a positive feedback loop between ZPA and ridge.