MOST ACCESSED ARTICLE – Blood Flow Regulates Zebrafish Caudal Vein Plexus Angiogenesis by ERK5-klf2a-nos2b Signaling

Journal Name: Current Molecular Medicine

Author(s): X. Xie, T. Zhou, Y. Wang, H. Chen, D. Lei, L. Huang, Y. Wang, X. Jin, T. Sun, J. Tan, T. Yin, J. Huang, H. Gregersen, G. Wang*.




Background: Vascular network formation induced by angiogenesis plays an important role in many physiological and pathological processes. However, the role of blood flow and underlying mechanisms in vascular network formation, for example for the development of the caudal vein plexus (CVP), is poorly understood.

Objective: The aim of this study was to explore the role of ERK5-klf2a-nos2b signaling in the CVP angiogenesis.

Method and Results: In this study on tnnt2a-MO injection and chemical blood flow modulator treatment in zebrafish embryos, we demonstrated that decreased blood flow disrupted CVP formation. The hemodynamic force was quantitatively analyzed. Furthermore, CVP angiogenesis in zebrafish embryos was inhibited by disruption of the blood flow downstream effectors ERK5, klf2a, and nos2b in response to treatment with the ERK5 specific inhibitor and to injection of klf2a-MO, nos2b-MO. Overexpression of klf2a mRNA or nos2b mRNA restored vascular defects in tnnt2a or klf2a morphants. The data suggest that flow-induced ERK5-klf2a-nos2b signaling is involved in CVP angiogenesis in zebrafish embryos.

Conclusion: We have demonstrated that blood flow is essential for vascular network formation, specifically for CVP angiogenesis in zebrafish. A novel genetic and mechanical mechanism was discovered in which ERK5 facilitates the integration of blood flow with the downstream klf2a-nos2b signaling for CVP angiogenesis.



EDITOR’S CHOICE – Role of Zebrafish fhl1A in Satellite Cell and Skeletal Muscle Development – Current Molecular Medicine

Journal: Current Molecular Medicine

Author(s):  F. Chen, W. Yuan, X. Mo, J. Zhuang, Y. Wang, J. Chen, Z. Jiang, X. Zhu, Q. Zeng, Y. Wan, F. Li, Y. Shi, L. Cao, X. Fan, S. Luo, X. Ye, Y. Chen, G. Dai, J. Gao, X. Wang, H. Xie*, P. Zhu*, Y. Li*, X. Wu


Background: Four-and-a-half LIM domains protein 1 (FHL1) mutations are associated with human myopathies. However, the function of this protein in skeletal development remains unclear.

Methods: Whole-mount in situ hybridization and embryo immunostaining were performed.

Results: Zebrafish Fhl1A is the homologue of human FHL1. We showed that fhl1A knockdown causes defective skeletal muscle development, while injection with fhl1A mRNA largely recovered the muscle development in these fhl1A morphants. We also demonstrated that fhl1A knockdown decreases the number of satellite cells. This decrease in satellite cells and the emergence of skeletal muscle abnormalities were associated with alterations in the gene expression of myoD, pax7, mef2ca and skMLCK. We also demonstrated that fhl1A expression and retinoic acid (RA) signalling caused similar skeletal muscle development phenotypes. Moreover, when treated with exogenous RA, endogenous fhl1A expression in skeletal muscles was robust. When treated with DEAB, an RA signalling inhibitor which inhibits the activity of retinaldehyde dehydrogenase, fhl1A was downregulated.

Conclusion: fhl1A functions as an activator in regulating the number of satellite cells and in skeletal muscle development. The role of fhl1A in skeletal myogenesis is regulated by RA signaling.

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Press Release for EurekAlert! Zebrafish as an animal model to study the effects of endocrine disruptors


Water is vital for our survival. However, water quality is always a concern for public health authorities as it may contain diverse environmental pollutants, including endocrine disrupting chemicals (EDCs). Endocrine disrupting chemicals are one group of potentially hazardous substances that comprise natural and synthetic chemicals, with the ability to mimic endogenous hormones or interfere with their biosynthesis, metabolism, and normal functions. Common examples are bisphenol A, triclosan, phthalates, lead, mercury, nickel and polychlorinated biphenyls, among others.

Fish are known to be quite sensitive to the effects of EDCs and therefore, are employed as research models to study the possible impacts of these chemicals in humans. In a review led by Purdue University (USA) and the University of Cartagena (Colombia), a team of researchers has proposed the zebrafish as a model to predict the effects of EDCs on humans using toxicogenomic tools, such as microarrays or whole-genome sequencing. This is possible due to the fact that zebrafish genes that have significantly altered expression after exposure to EDCs are very similar to those found in humans. In addition, many of the glandular system found in zebrafish have similarities with those in humans, making this fish model suitable to study alterations on the endocrine system.

According to the authors, vitellogenin and aromatase cytochrome P450 are key genes that can be monitored in zebrafish to detect the presence of EDCs in water samples, especially at environmentally relevant concentrations.

Toxicogenomic tools also offer the possibility to find new mechanisms by which EDCs alter the reproductive status of zebrafish, allowing its use to test the safety of new products entering the market. The possibilities are immense and the goal is to continue finding new markers of toxicity, and therefore alternative bridges to link EDC exposure to common diseases in humans.

Co-authors of the paper include Karina Caballero-Gallardo, Jesus Olivero-Verbel (University of Cartagena, Cartagena, Colombia) and Jennifer L. Freeman (Purdue University, USA).

Reference: Caballero-Gallardo, K.; et al (2016). Toxicogenomics to Evaluate Endocrine Disrupting Effects of Environmental Chemicals Using the Zebrafish Model., DOI: 10.2174/1389202917666160513105959

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Genetic Clue to How Limbs Evolved From Fins

Fish have the genetic machinery necessary to make fingers, but it is not switched on, a study suggests.


The research in Plos Biology journal sheds light on how fish evolved into the earliest land animals millions of years ago.

For fish to make the transition to land, an existing DNA architecture had to be “hijacked” in order to make digits, the researchers said.

In order to do this, they took genes from fish and inserted them into mice.

It was already known that the genes for limbs are found in fish but how they evolved to form digits remained unclear.

To unravel the genetics, the authors used the zebrafish as a model. But other scientists said that zebrafish were not a useful species for studying limb evolution.

Lead author Joost Woltering from the University of Geneva, Switzerland, said that he was interested in the “longstanding evolutionary question – how did limbs actually develop out of ancestral fish fins?”

In order to answer this, Dr Woltering and his colleagues looked at the genetics of fin and limb developments in zebra fish and mice.

He was particularly interested in the division of the hand and arm (or digits), which does not exist in fish fins and “is considered one of the major morphological innovations during the fin-to-limb transition”.


‘Architect’ genes

Tetrapods, the first four-legged creatures to walk the Earth, evolved from water to land over 380 million years ago in an era known as the Devonian period, often referred to as “the age of fish”.

Fish and land animals both have clusters of genes called HoxA and HoxD and both are known to be essential in fin and limb development.

These Hox genes are sometimes referred to as “architect genes” as they are involved in making many of the physical structures animals possess.

However, when these Hox genes from fish were placed into mouse embryos, the genes that result in the arm were switched on but not the genes responsible for the hand or the digits.

This suggests that the genetic information needed to make tetrapod limbs was already present in fish before the tetrapods evolved.

“During embryogenesis it is key that developmental genes are switched on at exactly the right time and right place to ensure the development of a complete, coherent good functioning adult organism,” Dr Woltering told BBC News.

Modernised genes

“The most surprising result is we found [DNA in fish] which is almost identical to the higher order DNA structure that we found in the mouse.”

Another important conclusion of the study is that fish fins are not equivalent to the tetrapod hand and digits. Instead, the evolution of digits in land animals involved the repurposing of existing genetic infrastructure.

One of the co-authors of the study, Prof Denis Duboule, also from the University of Geneva, said: “Altogether, this suggests that our digits evolved during the fin-to-limb transition by modernisation of an already existing regulatory mechanism.”

Other researchers in the field say that the study contains some flaws.

Jennifer Clack, from the Cambridge University Museum of Zoology, who was not involved with the study, said using the zebrafish as a model for the experiments was a bad choice.

“We know that this animal, and by inference its relatives… lack some of the developmental stages that make digits in tetrapods,” she explained.

Prof Clack added that other finned fish such as Polydon [paddlefish] “do have that mechanism, operating in a similar way to that in tetrapods, to make a complex fin skeleton”.

This suggests, she said, that the zebrafish at some point lost the ability to make digits.

This view was echoed by Per Ahlberg from the University of Uppsala, Sweden. He said that the molecular analysis was of a very high quality but that the evolutionary conclusions were flawed.


“This entire inference is based on the assumption that the zebrafish fin skeleton is reasonably representative of the ancestral condition for tetrapods, and it just isn’t,” he explained.

“Essentially, modern-day sturgeon, gar and bowfin (living primitive ray-finned fishes) have fin skeletons that are reasonably close to the shared ancestral condition for mouse and zebrafish.”

[Source: BBC News]

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