Researchers replicate a potential step of the fin-to-limb transition in zebrafish

February 04, 2021

By tweaking a single gene, Harvard scientists engineered zebrafish that show the beginning formation of limb-like appendages. The researchers stumbled upon this mutation, which may shed light on the sea-to-land transition of vertebrates, while screening for various gene mutants and their impact on fish development. Their discovery, outlined February 4th in the journal Cell, marks a fundamental step in our understanding of fin-to-limb evolution and how surprisingly simple genetic changes can create great leaps in the development of complex structures.

"It was a little bit unbelievable that just one mutation was able to create completely new bones and joints," says M. Brent Hawkins (@Homeobox), first author of the study, who recently received his doctorate from Harvard Organismic and Evolutionary Biology. "In the 30,000 species of teleost fishes, none of them have this sort of variation, so the fact that we found a mutant like this really knocked us off our feet."

The mutation Hawkins and colleagues discovered causes a change in in the zebrafish's pectoral fin bones called "proximal radials," which attach to the fish shoulder joint, similar to how the human arm attaches to our shoulder. But unlike humans and other tetrapods, zebrafish do not have series of these skeletal elements that articulate at joints, such as the components of our arm and fingers. With this mutation, a new set of long bones called "intermediate radials" develop and are able to articulate with the existing proximal radials, making a joint similar to our elbow.

"In this one mutation, you get the new bone, you make the joint, and you make the muscle attachments all in one go," says senior author Matthew Harris (@fishyskeleton), an associate professor of Genetics at Harvard Medical School and Orthopedics at Boston Children's Hospital. "You didn't need to have a mutation in the muscle gene, a joint gene, and in the bone gene; the system is coordinated such that whatever our change is, it's able to push all these things together in unison."

Genetic analysis revealed that mutations in either of two genes, vav2 and waslb, can independently cause this developmental change. Neither gene has previously been connected to skeletal development, but the analysis revealed that both genes activate Hox programs that pattern the middle region of the limb. "With these zebrafish, we're able to actually show that these mutations are activating programs that are quintessentially thought to be only found in a limb," says Harris. "So not only do we have the phenotype of something never before seen in teleost fish, but we show we can turn on ancestral patterns that were thought to be only limb associated."

Limbs are thought to be a key evolutionary innovation, allowing vertebrates to walk on land and--in the case of birds and bats--fly. What these results show is that a group of fishes who were thought to have either lost or silenced the machinery necessary to evolve limb-like appendages actually retain an innate latency to form these structures. "With our work, we've found unexpected commonalities between fins and limbs, and I think there are even more similarities that are yet to be discovered," says Hawkins.

Despite these findings, a question still remains of whether these new bones change the functionality of the zebrafish pectoral fins. Next steps will incorporate fine-scale video microscopy to determine whether the articulation of these news bones is enough to influence how the fish move. "Normally, the structures are not present to allow for the articulation required for movement on land," says Harris. "It'd be very interesting to see, for example, if we put our mutant on a platform, whether they would have an adjusted gate."

With the discovery of these mutants, researchers open a new line of questions on how vertebrates took their first steps towards movement on land, and of the genetic and developmental mechanics necessary to make it a happen. "While it's not the whole story, what we're seeing is a window into the puzzle of how you go from a fin to the modern limb," says Hawkins.

"And for me, I'm left with what can these mutants tells us about development and the ability to form complex structures. It's great reminder that not all monsters are scary. If you look closely, sometimes they can actually tell you a lot about yourself," says Harris.
This study was supported by the National Science Foundation and the Children's Orthopedic Research Foundation.

Cell, Hawkins et al.: "Latent developmental potential to form limb-like skeletal structures in zebrafish"

Cell (@CellCellPress), the flagship journal of Cell Press, is a bimonthly journal that publishes findings of unusual significance in any area of experimental biology, including but not limited to cell biology, molecular biology, neuroscience, immunology, virology and microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. Visit: To receive Cell Press media alerts, contact

Cell Press

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to