Researchers at the University of Eötvös Loránd (ELTE) have created a new disease model that has contributed to a better understanding of Bloom’s syndrome and zebrafish sex-determination processes. The studywhich links two apparently unrelated topics, was carried out by the research teams of Mihály Kovács (Department of Biochemistry) and Máté Varga (Department of Genetics) and was published in the scientific journal Cell death and disease. In addition to providing important information on the cellular effects of Bloom’s syndrome, the new model could contribute to the development of compounds capable of relieving symptoms and thus improving the quality of life for people with the disease.
Bloom syndrome is a rare genetic disease characterized by short stature, low fertility, red lesions on the skin when exposed to sunlight, and an increased risk of cancer, leading to early death.
The symptoms are caused by a defect in one gene that was also called Bloom, as well as the protein that it encodes.
Bloom and the other four members of his protein family are involved in many cellular processes responsible for maintaining DNA integrity, and their roles often overlap, making the task of studying the syndrome critically challenging. The importance of revealing the functional roles of Bloom is exacerbated by the fact that by inhibiting it, the survival and growth of some cancer cells may be impeded.
Due to its complexity, it is useful to examine diseases such as Bloom syndrome not only using cell cultures and computer models, but also by involving whole organisms. There are many vertebrates (African clawed frog, house mouse, brown mouse, house rabbit) and invertebrates (roundworm, fruit fly) used in “in vivo” studies worldwide. In the past decades zebrafish have also become a major member of this group.
Zebrafish as a disease model
Their advantage is that they are easy to keep, relatively small in size, and produce many fast-growing offspring that develop outside the parents’ bodies. Although they differ greatly from humans at first glance, their genetic material is remarkably similar as evidenced by the fact that 82% of the genes associated with human diseases have zebrafish counterparts. Bloom is one of these genes, allowing researchers to create mutations in order to study the symptoms of the mutation.
“The disease model developed by our researchers showed a remarkable similarity to human Bloom syndrome, yet a number of species-specific novelties were also revealed. The first such finding is that the early development of zebrafish was not hampered by the absence of Bloom protein, moreover there were no Marked differences between Blm-deficient fish and healthy fish even after they have been exposed to DNA-damaging treatments. This is likely due to lack of compensation for Bloom with other Bloom family proteins in young individuals” – Munda Tamas AnosAnd The first author of the publication, a doctoral student in the DanioLab research group in the Department of Genetics at Eötvös Loránd University.
However, this compensatory effect is not complete because according to the analysis of long life like many humans with Bloom syndrome, zebrafish also live shorter lives. When analyzing the success of fertilization, it was discovered that, like humans, mutant zebrafish show reduced fertility compared to their healthy mates. However, this effect could only be studied in male fish, as an additional curiosity of the mutant group was that it was composed entirely of males. Complete sex bias in zebrafish mutants is not a rare phenomenon, but to understand it we need to say a few words about sex determination in this species of fish.
A new animal model could contribute to the development of compounds capable of relieving symptoms
In contrast to zebrafish living in the wild, strains of domesticated laboratory zebrafish do not have sex chromosomes: in their absence sex development is regulated by the combined effects of many genes spread across the genome as well as environmental factors. These processes converge to regulate the number of reproductive stem cells that have not yet committed to developing into eggs or sperm cells. If the number of these cells reaches a critical threshold during a certain stage of development, the individual will develop as a female, otherwise as a male.
In the absence of the proteins responsible for maintaining the integrity of the DNA, these cells cannot reproduce to the amount required for female growth even if it is possible according to the above factors, resulting in all Bloom mutants turning into males. As an additional consequence of the mutation, sperm production is also affected which leads to a significant reduction in the success of fertilization compared to healthy fish.
“In the future, this model may provide additional valuable information about the regulation of the processes needed to determine the sex of zebrafish and the cellular effects of Bloom syndrome that, over time, may contribute to improving the quality of life of people living with this disorder via development of compounds capable of relieving symptoms.” – tamas Andras Summarize the results.
In the project, which was funded by the Laboratories of the National Office for Research, Development and Innovation of the Department of Genetics and the Department of Biochemistry, they joined colleagues at the Eötvös Loránd Research Network Institute of Enzymology and the Hungarian University of Agriculture and Life Sciences.
Cell death and disease
Bloom syndrome helicase contributes to germ line development and longevity in zebrafish
The date the article was published
April 18 2022
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