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Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):803-8. doi: 10.1073/pnas.1420208112. Epub 2014 Dec 22.

Deep conservation of wrist and digit enhancers in fish.

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Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, IL 60637;
Instituto de Ciencias Biologicas, Universidade Federal do Para, 66075, Belem, Brazil;
Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Sevilla 41013, Spain; and.
Institute of Neuroscience, University of Oregon, Eugene, OR 97403-1254.
Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, IL 60637;


There is no obvious morphological counterpart of the autopod (wrist/ankle and digits) in living fishes. Comparative molecular data may provide insight into understanding both the homology of elements and the evolutionary developmental mechanisms behind the fin to limb transition. In mouse limbs the autopod is built by a "late" phase of Hoxd and Hoxa gene expression, orchestrated by a set of enhancers located at the 5' end of each cluster. Despite a detailed mechanistic understanding of mouse limb development, interpretation of Hox expression patterns and their regulation in fish has spawned multiple hypotheses as to the origin and function of "autopod" enhancers throughout evolution. Using phylogenetic footprinting, epigenetic profiling, and transgenic reporters, we have identified and functionally characterized hoxD and hoxA enhancers in the genomes of zebrafish and the spotted gar, Lepisosteus oculatus, a fish lacking the whole genome duplication of teleosts. Gar and zebrafish "autopod" enhancers drive expression in the distal portion of developing zebrafish pectoral fins, and respond to the same functional cues as their murine orthologs. Moreover, gar enhancers drive reporter gene expression in both the wrist and digits of mouse embryos in patterns that are nearly indistinguishable from their murine counterparts. These functional genomic data support the hypothesis that the distal radials of bony fish are homologous to the wrist and/or digits of tetrapods.


Hox; autopod; development; evolution; gene regulation

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