Fig. 9. Model linking skeletal size determination with digit separation in the developing mouse limb. In this model [adapted from Mariani and Martin (Mariani and Martin, 2003)], N-Myc acts downstream of AER-derived FGFs in regulating the pool of undifferentiated mesenchyme (green) in the early limb bud. The undifferentiated mesenchyme gives rise to precartilaginous condensations that are pre-specified to generate proximal [stylopod: forelimb humerous (blue)], medial [zeugopod: forelimb radius and ulna (yellow)] and distal (autopod, red) skeletal elements. After contributing to the growth of the limb segments, residual undifferentiated cells are localized to the IDM, where they contribute to the final stages of autopod patterning and are then eliminated by programmed cell death. Their elimination terminates autopod patterning and initiates digit separation. In the absence of N-Myc, the pool of undifferentiated mesenchymal cells is reduced, leading to a proportional decrease in all skeletal segments. The reduced pool of undifferentiated mesenchymal cells is depleted during skeletal outgrowth, leading to loss of the undifferentiated IDM that is targeted for cell death and required for digit separation.