Interacting FGF and WNT cascades are critical in early limb induction, AER formation and reciprocal epithelial- mesenchymal interactions necessary for AER maintenance

The limb bud is induced in the lateral plate mesoderm in response to signals thought to be relayed in several steps from the embryo midline to the periphery (reviewed by Martin, 1998). Growth and patterning of the limb bud is organized by three signaling centers that arise before or soon after initial budding, and whose activities polarize pattern formation along the three axes of the limb: anteroposterior (AP), dorsoventral (DV), proximodistal (PD). Multiple cross-regulatory interactions between these signaling centers further coordinate development. Limb outgrowth along the PD axis is regulated by FGF signals from a specialized columnar ectoderm that normally forms along the DV boundary at the limb apex, the apical ectodermal ridge (AER) (reviewed by Martin, 1998; Lewandoski et al., 2000; Moon and Capecchi, 2000; Sun et al., 2002). Interacting FGF and WNT cascades are critical in early limb induction, AER formation and reciprocal epithelialmesenchymal interactions necessary for AER maintenance (reviewed by Martin, 1998; Tickle and Munsterberg, 2001). Several WNTs and FGFs, acting directly or indirectly, are able to induce ectopic limbs in the flank (e.g. Cohn et al., 1995; Ohuchi et al., 1997; Kawakami et al., 2001). Ultimately, FGF10 in the prospective limb lateral plate induces ectodermal Wnt (Wnt3a in chick) and Fgf8 expression in the forming AER (Ohuchi et al., 1997; Kengaku et al., 1998; Galceran et al., 1999). FGF8 from the AER ectoderm also maintains high level Fgf10 expression in limb mesoderm. Thus, reciprocal FGF8 and FGF10 signals form a positive regulatory loop by which AER and subridge mesoderm functionally maintain each other (Ohuchi et al., 1997; Revest et al., 2001). Sonic hedgehog (Shh), expressed in posterior limb bud mesoderm, regulates AP polarity and number of skeletal elements. Activation of Shh also depends on ridge signals and subsequently positive feedback between FGF4 from posterior ridge and SHH maintains both signaling centers (reviewed by Capdevila and Johnson, 2000). AER induction, as well as later maturation, is normally closely linked to DV boundary formation although they can be uncoupled (reviewed by Zeller and Duboule, 1997; Tickle and Munsterberg, 2001). Early upstream BMP signaling regulates 1327 Development 130, 1327-1337 S. Mackem, 2003 Published by The Company of Biologists Ltd doi:10.1242/dev.00354