Rare Genetic Blood Disease Modeling in Zebrafish

Abstract

Hematopoiesis results in the correct formation of all the different blood cell types. In mammals, it starts from specific hematopoietic stem and precursor cells residing in the bone marrow. Mature blood cells are responsible for supplying oxygen to every cell of the organism and for the protection against pathogens. Therefore, inherited or de novo genetic mutations affecting blood cell formation or the regulation of their activity are responsible for numerous diseases including anemia, immunodeficiency, autoimmunity, hyper- or hypo-inflammation, and cancer. By definition, an animal disease model is an analogous version of a specific clinical condition developed by researchers to gain information about its pathophysiology. Among all the model species used in comparative medicine, mice continue to be the most common and accepted model for biomedical research. However, because of the complexity of human diseases and the intrinsic differences between humans and other species, the use of several models (possibly in distinct species) can often be more helpful and informative than the use of a single model. In recent decades, the zebrafish (Danio rerio) has become increasingly popular among researchers, because it represents an inexpensive alternative compared to mammalian models, such as mice. Numerous advantages make it an excellent animal model to be used in genetic studies and in particular in modeling human blood diseases. Comparing zebrafish hematopoiesis to mammals, it is highly conserved with few, significant differences. In addition, the zebrafish model has a high-quality, complete genomic sequence available that shows a high level of evolutionary conservation with the human genome, empowering genetic and genomic approaches. Moreover, the external fertilization, the high fecundity and the transparency of their embryos facilitate rapid, in vivo analysis of phenotypes. In addition, the ability to manipulate its genome using the last genome editing technologies, provides powerful tools for developing new disease models and understanding the pathophysiology of human disorders. This review provides an overview of the different approaches and techniques that can be used to model genetic diseases in zebrafish, discussing how this animal model has contributed to the understanding of genetic diseases, with a specific focus on the blood disorders.

Validation of a Novel Zebrafish Model of Dengue Virus (DENV-3) Pathology Using the Pentaherbal Medicine Denguenil Vati

“…In silico analysis identified that it is a potent inhibitor of the NS2B-NS3 receptor in dengue virus [ 39 ]. The acemannan carbohydrate polymers present in Aloe vera facilitate phagocytosis by acting as a bridge between foreign proteins, such as virus particles and macrophages [ 40 ], and reduce hepatic damage by inhibiting necrosis and mononuclear cell infiltration [ 25 , 41 ]. Carica papaya leaf extracts exert antidengue properties by decreasing intracellular viral load [ 42 ].…”

“…Further, its remarkable similarities to the human system and signaling pathways involved in the immune response has made zebrafish a greatly used model to research host–pathogen interactions, including viral infections and antiviral drug screening, hence providing original therapeutic avenues [ 23 ]. Further, use of zebrafish for disease modelling of rare genetic blood diseases and for drug discovery in Parkinson’s disease and other movement disorders is apparent [ 24 , 25 ]. In the context of viral infections, zebrafish models have unexpected idiosyncrasies among organs that may apply to the human situation [ 22 ].…”

The contribution of fish models in understanding of blood disorders

“…Zebrafish csf3r mutants with significantly decreased numbers of neutrophils from embryonic to adult stages, did not respond to Granulocyte colony-stimulating factor (G-CSF), and displayed enhanced susceptibility to bacterial infection (Pazhakh et al, 2017;Basheer et al, 2019). WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome is a congenital immune deficiency characterized by hypogammaglobulinemia, infections, myelokathexis (retention of neutrophils in the bone marrow), leukopenia, human papillomavirus (HPV)-induces warts, reduced long-term immunoglobulin G (IgG) titers and severe chronic neutropenia (Kawai and Malech, 2009;Rissone and Burgess, 2018). WHIM syndrome is caused by a gain in function mutation in CXCR4 (CXC chemokine receptor 4) that induce the truncation of its carboxy-terminal domain (Rissone and Burgess, 2018).…”

“…WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome is a congenital immune deficiency characterized by hypogammaglobulinemia, infections, myelokathexis (retention of neutrophils in the bone marrow), leukopenia, human papillomavirus (HPV)-induces warts, reduced long-term immunoglobulin G (IgG) titers and severe chronic neutropenia (Kawai and Malech, 2009;Rissone and Burgess, 2018). WHIM syndrome is caused by a gain in function mutation in CXCR4 (CXC chemokine receptor 4) that induce the truncation of its carboxy-terminal domain (Rissone and Burgess, 2018). Danio rerio was used for studying this disease because it allows visualization of the neutrophils circulation due to transparency.…”

“…Rag2-EGFP-mMyc Langenau et al, 2003Rag2-NOTCHCD-EGFP Chen et al, 2007Ef1 alpha: EGFP-TEL-AML1 Sabaawy et al, 2006 Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder characterized through microthrombocytopenia, recurrent infections, eczema, bloody diathesis and a high frequency of autoimmunity and malignancy (Rissone and Burgess, 2018;Mansour et al, 2020). This disorder is caused by mutations in the WAS gene which encodes WAS protein (WASp).…”