Now researchers at the Salk Institute for Biological Studies have identified an essential cellular pathway in zebrafish that paves the way for limb regeneration by unlocking gene expression patterns last seen during embryonic development. They found that a process known as histone demethylation switches cells at the amputation site from an inactive to an active state, which turns on the genes required to build a copy of the lost limb.
"This is the first real molecular insight into what is happening during limb regeneration," says first author Scott Stewart, Ph.D., a postdoctoral researcher in the lab of Juan Carlos Izpisúa Belmonte, Ph.D., who led the Salk team. "Until now, how amputation is translated into gene activation has been like magic. Finally we have a handle on a process we can actually follow."
Their findings, which will be published in a forthcoming issue of Proceedings of the National Academy of Sciences, U.S.A., help to explain how epimorphic regeneration—the regrowing of morphologically and functionally perfect copies of amputated limbs—is controlled, an important step toward understanding why certain animals can do it and we cannot.
"Our experiments show that normal development and limb regeneration are controlled by similar mechanisms," explains Izpisúa Belmonte, a professor in the Gene Expression Laboratory. "This finding will help us to ask more specific questions about mammalian limb regeneration: Are the same genes involved when we amputate a mammalian limb? If not, what would happen if we turned them on? And if we can affect these methylation marks in an amputated limb, what effect would that have?"
The Belmonte lab uses zebrafish, a small fish from the minnow family, to study limb regeneration. "If you amputate the tail of the zebrafish, it regenerates in about a week, seemingly with no effort and leaving no scar," explains Stewart. "What's more, it regenerates a perfect copy and—like growing grass—it will do this over and over again."Since regeneration recapitulates in broad strokes embryonic development, during which a complex multi-cellular organism develops from a handful of embryonic stem cells, the researchers began by comparing gene expression patterns between the two processes. During development, genes within specific cell types are turned on and off to trigger the necessary expression patterns that create a whole animal. Once their job is done, they lie silently till they are turned on once again following amputation.
Stewart discovered that the histone modifications that poise embryonic stem cell–specific genes for activation are also found on the histones near genes involved in regeneration, putting them into a ready-to-go state. "This suggests that two different gene expression programs may exist; one for normal cellular activity and one for regeneration," explains Stewart. To test this hypothesis, the team looked at the histone marks during regeneration. As suspected, they saw a reduction in "off" switches and an increase in "on" switches in regenerating tissue, tipping the balance toward gene expression.
Delving deeper, the researchers found that enzymes that remove the "off" mark, so-called demethylases, are present in high levels in regenerating tissue. One enzyme in particular, called Kdm6b.1, is found exclusively in cells that are undergoing the regeneration process. Without Kdm6b.1, zebrafish failed to regenerate amputated fins, meaning removal of the "off" mark is a prerequisite for fin regeneration.
In the long term, the Salk researchers hope that these findings will help them understand whether we can affect the outcome of mammalian limb regeneration. In the more immediate future, the team plans to use global approaches to identify all the targets of Kdm6b.1 during regeneration, and to find out what gives the signal to turn these genes off when regeneration is complete.
In addition to Stewart and Izpisúa Belmonte, Zhi-Yang Tsun, also contributed to the study.
The study was funded in part by the California Institute for Regenerative Medicine, the Fundacion Cellex, the G. Harold and Leila Y. Mathers Charitable Foundation, the Ipsen Foundation, and the National Institutes of Health.
About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes, and cardiovascular disorders by studying neuroscience, genetics, cell and plant biology, and related disciplines.
Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.
Gina Kirchweger | EurekAlert!
The world's tiniest first responders
21.06.2018 | University of Southern California
A new toxin in Cholera bacteria discovered by scientists in Umeå
21.06.2018 | Schwedischer Forschungsrat - The Swedish Research Council
In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.
Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...
Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.
Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
21.06.2018 | Life Sciences
21.06.2018 | Earth Sciences
21.06.2018 | Life Sciences