Trends in Cell Biology
Science & SocietySpecial Issue: Translational Cell BiologyOf fish and men: using zebrafish to fight human diseases
Section snippets
Disease modeling: is the zebrafish the new mouse?
Understanding and fighting diseases require the right tools. Some aspects of disease biology and treatment, such as tissue homeostasis, interactions between cells and their microenvironment, and response to drugs, cannot be fully recapitulated in vitro. There is thus a clear need for reliable animal models. Over the past 20 years, the mouse (Mus musculus) has become the inescapable preclinical model. Despite its strengths as a mammalian system, the mouse has experimental limitations that
Insights from zebrafish models
Numerous fish models of human diseases have been generated and studied, ranging from blood disorders and muscular dystrophies to neurodegenerative syndromes and cancer [4] (Figure 1). To illustrate the use of zebrafish for disease modeling, we first focus on selected blood disorders, which constitute the first human pathologies modeled in fish, in part due to the high degree of conservation of hematopoiesis between fish and human. Because cancer modeling in zebrafish has also become a field of
From tank to bedside
The possibility of collecting thousands of synchronized zebrafish embryos as well as their easy handling make them particularly amenable to chemical treatment. Accordingly, numerous chemical screens have been successfully performed in the fish [12]. One such screen looking for chemicals that would block formation of the neural crest, from which melanocytes arise, led to the identification of leflunomide, an inhibitor of pyrimidine synthesis [13]. Leflunomide was shown to trigger a pause in the
Concluding remarks: the translational future of the zebrafish
The generation of faithful zebrafish models is fueled by our knowledge of the genetics of human diseases. The recent development of deep-sequencing strategies on large sets of human tumor samples may yield novel insights into the genetic determinants of malignant transformation. Accordingly, the number of zebrafish models of cancer will continue to rise. The range of available techniques for the manipulation of zebrafish is increasing, thus offering new options to build models. Similar to
Disclaimer statement
L.I.Z. is a founder and stockholder of Fate, Inc. and Scholar Rock and a scientific advisor for Stemgent.
Acknowledgments
The authors thank Elliott J. Hagedorn for critical reading of the manuscript. This work was supported by NIH grant 5 R01 CA103846-10. In addition, L.I.Z. is a Howard Hughes Medical Institute Investigator and J.A. received support from the Foundation Bettencourt–Schueller.
References (15)
Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family
Blood
(2008)L-Leucine improves the anemia and developmental defects associated with Diamond–Blackfan anemia and del(5q) MDS by activating the mTOR pathway
Blood
(2012)T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation
Cancer Cell
(2010)BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma
Curr. Biol.
(2005)The zebrafish reference genome sequence and its relationship to the human genome
Nature
(2013)Zebrafish xenografts as a tool for in vivo studies on human cancer
Ann. N. Y. Acad. Sci.
(2012)- et al.
Systematic approaches to toxicology in the zebrafish
Annu. Rev. Pharmacol. Toxicol.
(2012)