International Journal of Marine Science, 2024, Vol.14, No.5, 332-340 http://www.aquapublisher.com/index.php/ijms 337 6.2 Investigating bardet-biedl syndrome with zebrafish models Bardet-Biedl Syndrome (BBS) is another ciliopathy that has been extensively studied using zebrafish models. BBS is characterized by retinal degeneration, obesity, polydactyly, and renal abnormalities. Zebrafish have been used to model the retinal degeneration observed in BBS, which is caused by dysfunction in photoreceptor ciliary-related proteins. These models have helped clarify the role of BBS proteins in the primary cilium and their interactions with other ciliary modules, such as the intraflagellar transport (IFT) module (Delvallée and Dollfus, 2023). The use of zebrafish has also enabled the study of the nephronophthisis (NPHP) module, which is involved in the transition zone of primary cilia, furthering our understanding of the molecular mechanisms leading to BBS (Wang et al., 2022). These insights are crucial for developing targeted therapies for BBS and related ciliopathies. 6.3 Insights into nephronophthisis from zebrafish studies Nephronophthisis (NPH) is a ciliopathy that primarily affects the kidneys, leading to cystic kidney disease. Zebrafish models have proven to be valuable in studying the genes associated with NPH. The transparency of zebrafish embryos and larvae allows for non-invasive imaging of ciliary phenotypes, facilitating the study of gene-specific knockdowns and their effects on ciliary function (Molinari et al., 2018). For example, imaging cilia within Kupffer's vesicle in zebrafish has been used to assess NPH-related phenotypes, providing detailed insights into the developmental structures affected by NPH genes. Zebrafish models have been used to investigate the variable phenotypes and penetrance of different ciliary transition zone mutants, which include NPH-associated genes. This research has highlighted the tissue-specific functions of these genes and the complex dynamics of ciliary phenotypes. These studies are essential for understanding the pathogenesis of NPH and identifying potential therapeutic targets. 7 Case Study: Zebrafish in the Study of Kidney and Liver Ciliopathies 7.1 Modeling autosomal recessive polycystic kidney disease (ARPKD) in zebrafish Autosomal recessive polycystic kidney disease (ARPKD) is a severe genetic disorder characterized by the formation of cysts in the kidneys and liver, primarily caused by mutations in the PKHD1 gene, which encodes the Fibrocystin/Polyductin (FPC) protein. Zebrafish have emerged as a valuable model for studying ARPKD due to their genetic and physiological similarities to humans. Research has shown that mutations in the DZIP1L gene, which encodes a ciliary-transition-zone protein, also contribute to ARPKD. Studies using zebrafish have demonstrated that DZIP1L localizes to centrioles and the distal ends of basal bodies, playing a crucial role in maintaining the periciliary diffusion barrier (Olson et al., 2019). This barrier is essential for the proper ciliary-membrane translocation of polycystin-1 and polycystin-2, proteins implicated in ARPKD pathogenesis (Song et al., 2016). 7.2 Zebrafish as a model for studying hepatic fibrosis Hepatic fibrosis, often associated with ciliopathies, is another area where zebrafish models have provided significant insights. The liver, like the kidney, is affected in ARPKD, leading to fibrosis and other complications. The FPC protein, encoded by PKHD1, is localized not only in the cilium but also in the basal body and other cellular compartments. This localization is crucial for understanding the unique tissue patterning events controlled by FPC, which are not influenced by polycystin-1 (PC1). Zebrafish models have been instrumental in elucidating these mechanisms, offering a clearer picture of how ciliary defects contribute to hepatic fibrosis and providing a platform for testing potential therapeutic interventions (Ma, 2020; McGrew, 2024). 7.3 Investigating the role of ciliary defects in hepatorenal ciliopathies Ciliary defects are central to the pathogenesis of hepatorenal ciliopathies, including ARPKD. The primary cilium, a cellular organelle, plays a pivotal role in maintaining renal tubule morphology and preventing cyst formation. In ARPKD, mutations in PKHD1 and DZIP1L disrupt the function and biogenesis of ciliary proteins such as FPC and polycystin-1/2. Zebrafish models have been crucial in studying these disruptions. For instance, while DZIP1L mutations compromise the ciliary expression of polycystin-1/2, FPC deficiency does not affect their biogenesis and localization, indicating divergent mechanisms leading to cyst formation. These findings underscore the complexity of ciliary functions and their impact on kidney and liver diseases, highlighting the importance of zebrafish as a model organism in this research area (Lu et al., 2017; Ma, 2020).
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