Signaling induced by FGFR2b-ligands interactionplays a critical function to control the amplification of the mesenchymal progenitors throughout limb development.

<p>(<b>A</b>) FGFR2b-ligands signaling plays a major function in the amplification of the mesenchymal cells that will give rise to the stylopod prior to limb bud induction. Transient inhibition of FGFR2b-ligands signaling at E8.5 is compatible with limb induction while inhibition at E9.5, 10.5 and E11.5 leads to the irreversible loss of the AER. (<b>B</b>) Consequences of Dox-IP at E8.5. In double heterozygous embryos, the mesenchymal progenitors that are specified to give rise to the stylopod are not amplified but the AER is induced at E9.5 allowing the formation and amplification of the mesenchymal progenitors for the <i>zeugopod</i> and autopod. Note that in our model the efficiency of the AER may not be the same as in WT as progenitors for Z and A are not amplified at the same rate leading to corresponding skeletal defects. In double homozygous embryos, the stylopod progenitors are not amplified and the AER is not functional (dotted line) leading to limb agenesis. (<b>C</b>) Consequences of Dox-IP at E10/E10.5. In double heterozygous embryos, the AER is lightly affected at E10.5 (dotted lined with big distances between gaps) the progenitors for the autopod are partially amplified leading to shorter digits. In <i>[R26^rtTA/+; Tg/Tg]</i> embryos, the AER is mildly affected at E10.5 (dotted line with smaller distance between gaps) the progenitors for the autopod are not amplified at all leading to absence of autopod. In double homozygous embryos, the AER is no longer functional at E10.5 (dotted line) and leads to absence of amplification of the mesenchymal progenitors for the zeugopod and autopod). (<b>C</b>) Schematic representation of the AER showing the superficial layer of periderm cells covering the compact AER cells expressing FGFR2b. FGFR2b ligand, FGF10 is expressed in the underlying mesenchyme. (<b>D</b>) FGFR2b signaling in the AER cells allows β-catenin stabilization. Such stabilization downstream of FGFR2b signaling, allows β-catenin function in cell adhesion and in signaling, <i>Fgf8</i>, <i>Dkk1</i> and <i>Wnt3</i> are known downstream targets.