Time Is Not of the Essence

Science Signaling  31 May 2011:
Vol. 4, Issue 175, pp. ec152
DOI: 10.1126/scisignal.4175ec152

Structures of the vertebrate limb develop in a proximal-to-distal sequence as the limb bud grows out from the flank. A prevalent model for the specification of cell fates along the proximodistal (PD) axis of the vertebrate limb is the progress zone model, in which the time spent in the limb bud mesenchyme determines cell fate. According to this cell-autonomous model, the more time a cell spends under the influence of fibroblast growth factor (FGF) and Wnt signals that emanate from the limb bud tip, the more distal the fate it adopts. Alternative models of non–cell autonomous specification invoke the role of proximal signals emanating from the flank, such as retinoic acid (RA), in the specification of proximal cell fates. Reports by Roselló-Díez et al. and Cooper et al. support the notion that combined inputs from proximal and distal signals cooperate to specify cell fates along the PD axis in the chick limb. Roselló-Díez et al. performed various transplantation experiments using excised limb buds and “recombinant limbs,” which consist of dissociated limb bud mesenchymal cells packed into ectodermal sheaths, that together revealed that formation of a complete PD axis depended upon both proximal and distal signals and that formation of proximal structures and expression of a proximal marker correlated with RA signaling. Cooper et al. demonstrated that RA signaling was required for proximal marker expression in limb bud mesenchymal cells that had been cultured with Wnt3a and FGF8 to maintain proliferation and suppress differentiation. Furthermore, transplantation experiments with recombinant limbs made from these cultured mesenchymal cells indicated that the presence of all three signals—RA, FGF, and Wnt—enabled formation of a complete PD axis despite the passage of time in culture. These results support a model in which proximal cell fate is determined nonautonomously by opposing extrinsic signals rather than autonomously by a clock mechanism. A Perspective by Mackem and Lewandoski discusses caveats to this model and the similarities between this model of limb cell specification in the embryonic chick limb bud and amphibian limb regeneration.

A. Roselló-Díez, M. A. Ros, M. Torres, Diffusible signals, not autonomous mechanisms, determine the main proximodistal limb subdivision. Science 332, 1086–1088 (2011). [Abstract] [Full Text]

K. L. Cooper, J. K.-H. Hu, D. ten Berge, M. Fernandez-Teran, M. A. Ros, C. J. Tabin, Initiation of proximal-distal patterning in the vertebrate limb by signals and growth. Science 332, 1083–1086 (2011). [Abstract] [Full Text]

S. Mackem, M. Lewandoski, Limb cells don't tell time. Science 332, 1038–1039 (2011). [Abstract] [Full Text]