Latent developmental potential to form limb-like skeletal structures in zebrafish
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Abstract
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.
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Hawkins et al. (2021) confirmed the presence of ancestral regulatory pathways in shaping limb-like forms in early fish.
“Hawkins et al. (2021) also confirmed the presence of ancestral regulatory pathways in shaping limb-like forms in early fish.”
From Ancestral developmental potentials in early bony fish contributed to vertebrate water-to-land transition (2021) · cites this paper as Hawkins et al. (2021)
Conditional knockout of Wasl in mice suggested that this gene regulatory pathway is required for normal limb pattern formation, and its absence results in a range of skeletal phenotypes that match those seen in Hoxa11-knockout mutants.
“Conditional knockout of Wasl in mice suggested that this gene regulatory pathway is required for normal limb pattern formation, and its absence results in a range of skeletal phenotypes that match those seen in Hoxa11-knockout mutants (Hawkins et al., 2021).”
From Ancestral developmental potentials in early bony fish contributed to vertebrate water-to-land transition (2021) · cites this paper as Hawkins et al., 2021
These ancestral features have been recreated in zebrafish by modifying their genetic makeup to reactivate the ancestral genetic network.
“Although certain ancestral features have been lost in teleosts, the most derived fish lineage to evolve after whole-genome duplication (Sato & Nishida, 2010), they have been recreated in zebrafish by modifying their genetic makeup to reactivate the ancestral genetic network (Hawkins et al., 2021).”
From Ancestral developmental potentials in early bony fish contributed to vertebrate water-to-land transition (2021) · cites this paper as Hawkins et al., 2021
Hawkins et al. (2021) identified two genes, Waslb and Vav2, which corresponded to the mutant phenotypes.
“They further identified two genes, Waslb and Vav2, which corresponded to the mutant phenotypes.”
From Ancestral developmental potentials in early bony fish contributed to vertebrate water-to-land transition (2021) · cites this paper as Hawkins et al., 2021
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References 99 · Cited by 80
- Authors
- Hawkins, M. B., Henke, K., & Harris, M. P.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Harris, Matthew P.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 184
- Issue
- 4
- Pages
- 899-911.e13
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W3128699789
- Cited by
- 80
- References
- 99
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 21 · 2023: 12 · 2022: 10 · 2021: 9 · 2020: 1 · 2019: 1
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California
- National Science Foundation (DEB-1600920)
- University of Chicago
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- fin-to-limb transition, pectoral fin development, appendage patterning, Vav2, WASL, HOX11, developmental homology, zebrafish mutants, vertebrate evolution
- MeSH terms
- Actins, Animals, Base Sequence, Bone and Bones, Epistasis, Genetic, Extremities, HeLa Cells, Humans, Mutation, Phenotype, Phylogeny, Zebrafish, Signal Transduction, Genes, Reporter, Homeodomain Proteins, Gene Expression Regulation, Developmental, Cell Lineage, Body Patterning, Zebrafish Proteins, Mice, Gene Knockout Techniques, Animal Fins, CRISPR-Cas Systems
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