Latent developmental potential to form limb-like skeletal structures in zebrafish

Cell. 2021 Feb 18;184(4):899-911.e13. doi: 10.1016/j.cell.2021.01.003. Epub 2021 Feb 4.


Changes in appendage structure underlie key transitions in vertebrate evolution. Addition of skeletal elements along the proximal-distal axis facilitated critical transformations, including the fin-to-limb transition that permitted generation of diverse modes of locomotion. Here, we identify zebrafish mutants that form supernumerary long bones in their pectoral fins. These new bones integrate into musculature, form joints, and articulate with neighboring elements. This phenotype is caused by activating mutations in previously unrecognized regulators of appendage patterning, vav2 and waslb, that function in a common pathway. This pathway is required for appendage development across vertebrates, and loss of Wasl in mice causes defects similar to those seen in murine Hox mutants. Concordantly, formation of supernumerary bones requires Hox11 function, and mutations in the vav2/wasl pathway drive enhanced expression of hoxa11b, indicating developmental homology with the forearm. Our findings reveal a latent, limb-like pattern ability in fins that is activated by simple genetic perturbation.

Keywords: N-WASP; VAV2; development; evolution; fin-to-limb transition; genetics; hox genes; patterning; skeletal biology; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism
  • Animal Fins / embryology
  • Animals
  • Base Sequence
  • Body Patterning
  • Bone and Bones / embryology*
  • CRISPR-Cas Systems / genetics
  • Cell Lineage
  • Epistasis, Genetic
  • Extremities / embryology*
  • Gene Expression Regulation, Developmental
  • Gene Knockout Techniques
  • Genes, Reporter
  • HeLa Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Mutation / genetics
  • Phenotype
  • Phylogeny
  • Signal Transduction / genetics
  • Zebrafish / embryology*
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism


  • Actins
  • Homeodomain Proteins
  • Zebrafish Proteins