Article | Published:

Patterning and post-patterning modes of evolutionary digit loss in mammals

Nature volume 511, pages 4145 (03 July 2014) | Download Citation


A reduction in the number of digits has evolved many times in tetrapods, particularly in cursorial mammals that travel over deserts and plains, yet the underlying developmental mechanisms have remained elusive. Here we show that digit loss can occur both during early limb patterning and at later post-patterning stages of chondrogenesis. In the ‘odd-toed’ jerboa (Dipus sagitta) and horse and the ‘even-toed’ camel, extensive cell death sculpts the tissue around the remaining toes. In contrast, digit loss in the pig is orchestrated by earlier limb patterning mechanisms including downregulation of Ptch1 expression but no increase in cell death. Together these data demonstrate remarkable plasticity in the mechanisms of vertebrate limb evolution and shed light on the complexity of morphological convergence, particularly within the artiodactyl lineage.

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Data deposits

The probe sequence data for all genes and species has been deposited in the NCBI Probes database with the following accession numbers: CAMELBMP4, Pr032067180; CAMELFGF8, Pr032067181; CAMELGLI1, Pr032067182; CAMELHOXD13, Pr032067183; CAMELPTCH1, Pr032067184; HORSEBMP4, Pr032067185; HORSEFGF8, Pr032067186; HORSEGLI1, Pr032067187; HORSEHOXD13, Pr032067188; HORSEMSX2, Pr032067189; HORSEPTCH1, Pr032067190; HORSESHH, Pr032067191; JERBOABMP4, Pr032067192; JERBOAFGF8, Pr032067193; JERBOAGLI1, Pr032067194; JERBOAHOXD13, Pr032067195; JERBOAMSX2, Pr032067196; JERBOAPTCH1, Pr032067197; JERBOASHH, Pr032067198; MOUSEBMP4, Pr032067199; MOUSEFGF8, Pr032067200; MOUSEGLI1, Pr032067201; MOUSEHOXD13, Pr032067202; MOUSEMSX2, Pr032067203; MOUSEPTCH1, Pr032067204; MOUSESHH, Pr032067205; PIGFGF8, Pr032067206; PIGPTCH1, Pr032067207; PIGSHH, Pr032067208.


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We thank J. Lopez-Rios and R. Zeller (University of Basel, Switzerland) for generously providing data and discussion before publication. We also thank J. Carlos Izpisua Belmonte and A. Aguirre for sharing space and materials to complete experiments subsequent to review. Jerboa embryos were harvested with the assistance of S. Wu and colleagues in Xinjiang, China. Pig embryos were harvested with the assistance of D. Urban. Additional horse embryos were provided by R. Turner and H. Galatino-Homer (University of Pennsylvania) and by R. Fritsche and S. Lyle (Louisiana State University). Mouse Gli1 probe plasmid, used in the pig in situ, was provided by A. Joyner. This work was supported by NIH grant R37HD032443 to C.J.T., and NSF IOS grant 1257873 to K.E.S.

Author information

Author notes

    • Kimberly L. Cooper

    Present address: Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA.

    • Kimberly L. Cooper
    • , Karen E. Sears
    •  & Aysu Uygur

    These authors contributed equally to this work.


  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Kimberly L. Cooper
    • , Aysu Uygur
    •  & Clifford J. Tabin
  2. Department of Animal Biology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA

    • Karen E. Sears
    •  & Jennifer Maier
  3. École Normale Supérieure de Lyon, 69007 Lyon, France

    • Karl-Stephan Baczkowski
  4. Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA

    • Margaret Brosnahan
    •  & Doug Antczak
  5. The Camel Reproduction Centre, Dubai, United Arab Emirates

    • Julian A. Skidmore


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K.L.C., K.E.S. and C.J.T. conceived of and initiated the project. K.L.C. and C.J.T. wrote the manuscript. K.L.C performed the mouse, three- and five-toed jerboa, horse and camel in situ hybridizations, PH3 IHC, and skeletal stains. A.U. performed TUNEL and Sox9 IHC. J.M. and K.E.S. performed the pig in situ hybridizations. K.-S.B. cloned the pig probes. M.B. and D.A. provided most of the horse embryos and material for cloning the horse probes. J.A.S. provided the camel embryos and material for cloning the camel probes.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kimberly L. Cooper or Karen E. Sears.

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