Understanding the evolutionary transformation of fish fins into tetrapod limbs is a fundamental problem in biology1. The search for antecedents of tetrapod digits in fish has remained controversial because the distal skeletons of limbs and fins differ structurally, developmentally, and histologically2,3. Moreover, comparisons of fins with limbs have been limited by a relative paucity of data on the cellular and molecular processes underlying the development of the fin skeleton. Here, we provide a functional analysis, using CRISPR/Cas9 and fate mapping, of 5′ hox genes and enhancers in zebrafish that are indispensable for the development of the wrists and digits of tetrapods4,5. We show that cells marked by the activity of an autopodial hoxa13 enhancer exclusively form elements of the fin fold, including the osteoblasts of the dermal rays. In hox13 knockout fish, we find that a marked reduction and loss of fin rays is associated with an increased number of endochondral distal radials. These discoveries reveal a cellular and genetic connection between the fin rays of fish and the digits of tetrapods and suggest that digits originated via the transition of distal cellular fates.
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We thank J. Westlund for figure preparation and construction, as well as maintenance of zebrafish facilities. M. Coates, M. Davis, R. Ho, I. Ruvinsky, J-L. Gomez Skarmeta, and C. Tabin provided comments and advice. We thank L. I. Zon, C. Mosimann, and C. Lawrence for Tg(ubi:Switch) fish, M. L. Suster for the pCR8GW-Cre-pA-FRT-kan-FRT plasmid, R. Ho and S. Briscoe for insights regarding lineage-tracing experiments, V. Bindokas and the University of Chicago Integrated Light Microscopy Core Facility for assistance with imaging, L. Zhexi for use of the high-energy CT scanning facility of University of Chicago, M. E. Horb and M. C. Salanga of the National Xenopus Resource (RRID:SCR-013731) of the Marine Biological Laboratories for tutelage in applying CRISPR/Cas9, J. Gitlin, A. Latimer and R. Thomason for providing space for zebrafish CRISPR/Cas9 experiments and also maintaining juveniles, and the Marine Resource Center of the Marine Biological Laboratories for assistance with the transfer of mutant zebrafish between University of Chicago and the MBL. This study was supported by the Uehara Memorial Foundation Research Fellowship 2013, Japan Society for the Promotion of Science Postdoctoral Research Fellowship 2012-127, and Marine Biological Laboratory Research Award 2014 (to T.N.); National Institutes of Health Grant T32 HD055164 and National Science Foundation Doctoral Dissertation Improvement Grant 1311436 (to A.R.G.); and the Brinson Foundation and the University of Chicago Biological Sciences Division (to N.H.S.).
Extended data figures
This file contains a 3D pdf of wild-type and double mutant fin.
About this article
Science Advances (2019)