Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How zebrafish rebuild the skeleton of amputated fins

17.08.2015

Researchers from Bayreuth University (Germany) uncover mechanisms that allow bone-forming cells to regenerate a correctly shaped new fin skeleton.

Fish, in contrast to humans, have the fascinating ability to fully regenerate amputated organs. The zebrafish (Danio rerio) is a popular ornamental fish. When parts of its tailfin are injured by predators, or are experimentally amputated, the lost tissue is replaced within three weeks. Zebrafish therefore are a favored animal model to study the cellular and molecular principles of organ regeneration.


Bone formation upon partial amputation of zebrafish tail fins. L: normal regeneration of fin rays; R: irregular bone formation with widely expanded production of the signaling protein Sonic Hedgehog.

Image: Developmental Biology, University of Bayreuth


The regenerating tissue (blastema) of a zebrafish tail fin after amputation.

Image: Developmental Biology, University of Bayreuth

Zebrafish fins consist of a skin that is stabilized by a skeleton of bony fin rays; similar to an umbrella that is supported by metallic stretchers. Fin rays are formed by bone-producing cells, the osteoblasts. In order to rebuild an amputated fin, a large number of new osteoblasts have to be formed by cell divisions from existing osteoblasts.

For this to happen, osteoblasts exposed to the vicinty of the wound have to abandon the production of bone material and revert, or dedifferentiate, to a "rejuvenated" developmental stage. Specialized mature cells, therefore, become osteoblast precursors, which is a requirement to begin several rounds of cell divisions.

Up to now only little was known about how changes in the differentiation status of osteoblasts are brought about, and it was unknown how zebrafish manage to regenerate the exact shape of the lost fin skeleton. Prof. Dr. Gerrit Begemann, at the Developmental Biology unit at the University of Bayreuth (Germany), and Ph.D. student Nicola Blum now report progress on both fronts, published in two articles in the "Advance Online Articles" section of the journal "Development". The new results are likely to inform efforts to reconstitute bone tissue and injured organs in humans.

A cell's dilemma of proliferation versus specialization

Retinoic acid is required to regulate the addition of bone material in growing fish. During regeneration, mature osteoblasts have to revert to an immature osteoblast precursor, which enables the switch from bone synthesis to cell division. The switch requires retinoic acid levels to drop below a critical concentration.

However, upon amputation the tissue beneath the wound initiates a massive bout of retinoic acid synthesis that is required to mobilize cell division in the fin stump. How do mature osteoblasts circumvent this dilemma?

The answer was provided by Nicola Blum in the laboratory of Prof. Dr. Gerrit Begemann: Osteoblasts that participate in regeneration transiently produce Cyp26b1, an enzyme that destroys and inactivates retinoic acid. Protected by this process, osteoblasts are able to rewind their developmental clocks, thus turning into precursor cells that contribute to a pool of undifferentiated cells, the blastema. Cells in the blastema pass through a number of cell divisions to provide the building blocks for the regenerated fin.

However, these cell divisions are supported by high concentrations of retinoic acid, which poses the next predicament: The reversion to become a mature osteoblast is inhibited by high levels of retinoic acid. Nicola Blum found out that connective tissue in those areas of the blastema from which new mature osteoblasts eventually emerge produces the retinoic acid killer Cyp26b1.

This lowers the local concentration of retinoic acid, so that osteoblast precursors are again able to mature and produce new fin rays. Other parts of the blastema, which replenish the supply of cells needed for regeneration to occur, continue to produce retinoic acid. "This is an elegant mechanism that ensures a gradient of cells experiencing high and low levels of retinoic acid", Begemann explains, "This allows two processes to run in parallel during regeneration: Proliferation for the production of all cells that replace the lost structure and redifferentiation of osteoblasts where the skeleton re-emerges."

A navigation system that routes cells to regenerating fin rays

How is the exact shape of the fin skeleton regenerated? In order to form new fin rays, newly formed osteoblasts have to align at the correct positions, in this case in extension of existing fin rays in the stump region. The mechanisms ensuring correct osteoblast alignment had remained unknown so far. In a second study, also published in "Development", Nicola Blum broke down the events required for skeletal pattern regeneration.

Osteoblasts are ultimately guided to target regions by a signaling protein called Sonic Hedgehog. This is produced locally in the epidermis, a skin-like layer that covers the fin and the blastema. However, signal production only occurs in locally restricted cells that are free of retinoic acid. Such epidermal cells produce Cyp26a1, an enzyme that is functionally similar to Cyp26b1.

By manipulating the levels of retinoic acid metabolism in a way that allows Sonic Hedgehog expression from most regenerating cells, Nicola Blum could show that Sonic Hedgehog acts as a beacon for osteoblast precursor cells. The consequences were dramatic: Instead of aligning with existing fin rays, the cells also invaded the spaces between them, which normally form elastic skin. Eventually bone also formed at inappropriate positions, which in turn sabotaged regeneration and the emergence of the original skeletal pattern.

Lastly, it emerged that osteoblasts themselves exert a piloting function for other cell types, particularly mesenchymal cells and blood vessels that also have to be directed to appropriate destinations during the rebuilding process. If osteoblast precursors are misguided, these cell types follow and exacerbate the inability to reform a functional fin skeleton.

"The re-emergence of the skeletal pattern relies on a navigation system with interacting parts", Begemann summarizes. "Initially, retinoic acid is inactivated where new rays are to form. This allows the local production of a signal that pilots immature osteoblasts to areas where existing fin rays are to be extended. Interestingly, over the course of regeneration other cell types in the blastema are informed by osteoblast precursors to respect the boundaries between emerging fin rays."

Publications:

Nicola Blum and Gerrit Begemann, Osteoblast de- and redifferentiation is controlled by a dynamic response to retinoic acid during zebrafish fin regeneration.
Development 2015, Vol 142 / Issue 17; posted ahead of print August 7, 2015,
doi: 10.1242/dev.120204

Nicola Blum and Gerrit Begemann, Retinoic acid signaling spatially restricts osteoblasts and controls ray-interray organization during zebrafish fin regeneration.
Development 2015, Vol 142 / Issue 17; posted ahead of print August 7, 2015,
doi: 10.1242/dev.120212

Contact:

Prof. Dr. Gerrit Begemann
Developmental Biology
University of Bayreuth
D-95440 Bayreuth
Telephone: +49 (0)921 55 2475
E-Mail: gerrit.begemann@uni-bayreuth.de

Christian Wißler | Universität Bayreuth
Further information:
http://www.uni-bayreuth.de/

Further reports about: Zebrafish acid blastema cell types retinoic retinoic acid skeletal

More articles from Life Sciences:

nachricht What the world's tiniest 'monster truck' reveals
23.08.2017 | American Chemical Society

nachricht Treating arthritis with algae
23.08.2017 | Empa - Eidgenössische Materialprüfungs- und Forschungsanstalt

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

What the world's tiniest 'monster truck' reveals

23.08.2017 | Life Sciences

Treating arthritis with algae

23.08.2017 | Life Sciences

Witnessing turbulent motion in the atmosphere of a distant star

23.08.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>