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Nat Commun. 2015 Sep 18;6:8108. doi: 10.1038/ncomms9108.

An intrinsic timer specifies distal structures of the vertebrate limb.

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Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC-Universidad de Cantabria), Santander 39011, Spain.
Bateson Centre, Department of Biomedical Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
Departamento de Anatomía y Biología Celular, Facultad de Medicina, Universidad de Cantabria, Santander 39011, Spain.


How the positional values along the proximo-distal axis (stylopod-zeugopod-autopod) of the limb are specified is intensely debated. Early work suggested that cells intrinsically change their proximo-distal positional values by measuring time. Recently, however, it is suggested that instructive extrinsic signals from the trunk and apical ectodermal ridge specify the stylopod and zeugopod/autopod, respectively. Here, we show that the zeugopod and autopod are specified by an intrinsic timing mechanism. By grafting green fluorescent protein-expressing cells from early to late chick wing buds, we demonstrate that distal mesenchyme cells intrinsically time Hoxa13 expression, cell cycle parameters and the duration of the overlying apical ectodermal ridge. In addition, we reveal that cell affinities intrinsically change in the distal mesenchyme, which we suggest results in a gradient of positional values along the proximo-distal axis. We propose a complete model in which a switch from extrinsic signalling to intrinsic timing patterns the vertebrate limb.

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