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

• Published in: Cell 2021-02, Vol.184 (4), p.899-911.e13
• Main Authors: Hawkins, M. Brent, Henke, Katrin, Harris, Matthew P.
• Format: Article
• Language: English
• Subjects: development; evolution; fin-to-limb transition; genetics; hox genes; N-WASP; patterning; skeletal biology; VAV2; zebrafish
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.01.003

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. [Display omitted] •Teleost fishes have simple fin endoskeletons that lack elaborations found in limbs•Mutations in the vav2/waslb pathway cause new distal elements to form in fins•Similar to the limb forearm, these new ‘middle’ fin bones require Hox11 activity•Teleost fishes have latent limb-like Hox programs that can elaborate the endoskeleton In contrast to limbs, teleost fish fins have a diminutive endoskeleton with few elements. Zebrafish with mutations in the waslb/vav2 pathway express limb-like Hox patterning mechanisms that drive the formation of new, fully integrated bones along the length of the fin, revealing in fins the presence of latent developmental programs once thought unique to limbs.