10:2427. doi: 10.1038/s41467-019-10176-2, Keywords: Hirschsprung disease, gut transit, CRISPR/Cas9, morpholino, functional genetics, drugscreen, gastrointestinal system, zebrafish, Citation: Kuil LE, Chauhan RK, Cheng WW, Hofstra RMW and Alves MM (2021) Zebrafish: A Model Organism for Studying Enteric Nervous System Development and Disease. The zebrafish (Danio rerio) is relatively a newcomer to the field of behavioral neuroscience. Dev. bioRxiv 2020.06.14.150938. doi: 10.1101/2020.06.14.150938, Howe, K., Clark, M. D., Torroja, C. F., Torrance, J., Berthelot, C., Muffato, M., et al. (2013). Such antibodies have been used to identify, at least eight neuronal subtypes in zebrafish using combined staining (Uyttebroek et al., 2010, 2013). Am. 382, 320–329. (2010). Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction. As mentioned in this review, the current general belief is that a defect in either migration, differentiation, proliferation or survival of enteric progenitors, causes the developmental defects observed in HSCR patients. Size matters: large copy number losses reveal novel Hirschsprung disease genes. A new division based on conserved transcriptional profiles has also been proposed, which is depicted by color alterations and labels in regular font (Lickwar et al., 2017). Biol., 21 January 2021 (2013). (2011). According to the genome sequencing data, the zebrafish shares 70% genes with humans and more than 84% of genes that cause human genetic diseases are present in the zebrafish, making it an excellent model for studying human gene functions, especially those that cause various human genetic diseases. PLoS Genet. (2013). Scientists use a variety of laboratory techniques to investigate the genetic cause of human diseases. The authors generated a quantitative approach to determine from the STMaps, the frequency and speed of peristaltic waves by generating cross-correlation maps. Fecal matter accumulated at the bottom of the plate, was measured over time by a spectrophotometer (Cassar et al., 2018). This chapter discusses the scientific reasons for that popularity; describing many examples of similarities between zebrafish and mammalian function and development; how zebrafish have been used to discover novel pathways or mechanisms of toxicity; and the use of zebrafish as a model for ecological risk assessment, especially for rapid hazard testing and as bridge between laboratory and field-based studies. The data obtained can be inferred by spatiotemporal maps (STMaps) of gut flow (Figure 2B) (Holmberg et al., 2007). Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury. Peristaltic function is disrupted in zebrafish lacking enteric neurons, which is shown by the absence of bowel movement in the STMaps. *Correspondence: Laura E. Kuil, l.kuil@erasmusmc.nl, †These authors have contributed equally to this work, Front. The enteric innervation is already functional by 5 dpf, when zebrafish larvae start feeding. The current pathophysiological model is that failure of NCCs to migrate, differentiate, proliferate or survive, thereby forming a functional ENS network, results in HSCR. (2017). A more sophisticated way to analyze not only the temporal frequency of motility, but also displacement along the anterior to posterior, and dorsal to ventral axis, has been recently reported (Ganz et al., 2018). The zebrafish (Danio rerio) is a fresh water fish that originates from Southeast Asia and is the premier nonmammalian vertebrate for genetics studies. 317, 508–522. The sacral neural crest contributes neurons and glia to the post-umbilical gut: spatiotemporal analysis of the development of the enteric nervous system. doi: 10.1242/dev.00912, Soret, R., Schneider, S., Bernas, G., Christophers, B., Souchkova, O., Charrier, B., et al. Finally, zebrafish are amenable to in vivo imaging modalities, genetic and environmental manipulations, electrophysiological recordings, and neurobehavioral studies, potentially allowing key mechanistic insights to be gained rapidly by traditional hypothesis-driven experiments. Bull. Sci. This further supports the notion that the alterations in microbiome are the result of altered gut motility. Zebrafish arl6ip1 is required for neural crest development during embryogenesis. 25, 1030–1042. Using the gene-editing tool CRISPR-Cas9, the research team performed a simple experiment using a zebrafish … A method that has been fruitful in validating HSCR candidate genes that affect ENS development in zebrafish, is the use of morpholinos (MOs). Available online at: https://dev.biologists.org/content/127/12/2763.long, Reichenbach, B., Delalande, J. M., Kolmogorova, E., Prier, A., Nguyen, T., Smith, C. M., et al. Front. De novo enteric neurogenesis in post-embryonic zebrafish from Schwann cell precursors rather than resident cell types. (2011). This method was used to predict GI safety issues of drug candidates, but can also be useful to search for compounds that stimulate bowel movement. Interestingly, disruption of zebrafish orthologs of another autism gene, the SH3 and multiple ankyrin repeat domains 3 (SHANK3), also altered gut motility. I have been reading a lot about zebrafish research lately and I thought it would be nice to share some of my favorite articles with you. 1981). (2018). 39:e82. Gastroenterology 155, 118–129.e6. Nat. 207, 4085–4094. As in other vertebrates, the zebrafish ENS is derived from the neural crest (Kelsh and Eisen, 2000). 122, 659–669. Zebrafish are highly prolific with a single female capable of spawning several hundred eggs every week. 21, 304–312. Dev. These reporter lines are widely used in the field and often have a cell-specific promoter or regulatory element, that drives expression of a fluorophore in the cells of interest. Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse. Unmarked tracking of shoaling . 9:347. doi: 10.3389/fneur.2018.00347, Wallace, A. S., and Burns, A. J. In the late 1960s, George Streisinger, who is considered the founding father of zebrafish research, first introduced this tiny slender fish as a vertebrate model for research on genetics and development at the University of Oregon. Zebrafish as an animal model for drug discovery in parkinson's disease and other movement disorders: a systematic review. Combining transplantation with the addition of chemical compounds that stimulate ENS development or make the ENS environment more favorable, could significantly improve transplantation outcomes (Lui et al., 2018; Zhao et al., 2020). Genet. Depending on conditions, the lifespan of zebrafish ranges from 3 to 5 years. The possibility of targeted knock-in single nucleotides in zebrafish, is valuable to analyze specific variants identified in HSCR patients, especially in the case of missense variants, when the CRISPR/Cas9 knockout might not accurately reflect the functional consequences of such variants. (2019). Comp. (2016). Although epigenetic mechanisms, including hypomethylation, have been suggested as a disease mechanism for HSCR [reviewed in Torroglosa et al. 12:dmm037762. Such study would be highly informative, as the complex ENS developmental process would be studied in vivo, as a whole, in developing zebrafish. (2005). A., Moore, H. D., Barbaric, I., et al. 63, 318–331. Hirschsprung disease, associated syndromes and genetics: a review. Physiol. doi: 10.1038/nrg2091, Liu, K., Petree, C., Requena, T., Varshney, P., and Varshney, G. K. (2019). This percentage seems to be even higher (82%) for proteins involved in disease development (Howe et al., 2013). Figure 1. (D) Schematic representation of ENS development in mammals. A., Freundlich, T., Weissman, T. A., Schoppik, D., Wang, X. C., Zimmerman, S., et al. Int. PLoS Biol. Immunohistochemical and ultrastructural analysis of the maturing larval zebrafish enteric nervous system reveals the formation of a neuropil pattern. 28, 345–357. This brand new article was submitted for Neuroscience 2012, which … Dev. (2019). J. Med. J. Hum. Rep. 9:6941. doi: 10.1038/s41598-019-43497-9, Bernier, R., Golzio, C., Xiong, B., Stessman, H. A., Coe, B. P., Penn, O., et al. Biol. Because fundamental electrical properties of the zebrafish heart are remarkably similar to those of the human heart, the zebrafish may be an appropriate model for studying human inherited arrhythmias. The transparency of zebrafish larvae allows non-invasive visualization of enteric neurons (A), peristalsis (B), and gut transit (C). The authors also showed zebrafish Glial fibrillary acidic protein (Gfap) immunohistochemistry staining where, enteric glia processes largely form an inner layer separating neuronal axons from the intestinal epithelium (Baker et al., 2019). In vivo visualization of the development of the enteric nervous system using a Tg(-8.3bphox2b:Kaede) transgenic zebrafish. More recently, researchers started to determine the neural crest transcriptome at a single-cell resolution in late embryonic, to early larval stage (Howard et al., 2020). The her4.3+ cells were defined as neural crest derived, post-migratory cells that retain proliferative and neurogenic potential throughout life (McCallum et al., 2020). Although a lot of effort has been made to study ENS development in zebrafish, some developmental dynamics remain unsolved. In the study describing the zebrafish rethu2846 mutant, the authors showed that heterozygous rethu2846/+ larvae could be used to identify susceptibly loci, by injecting a MO in the heterozygous rethu2846/+ and wildtype larvae (Heanue et al., 2016). Three other mutants with ENS defects were also found in this forward genetic screen, and are listed in Table 1. Zebrafish foxd3 is selectively required for neural crest specification, migration and survival. Methods 49, 275–281. We thank Veerle Melotte for her helpful comments on the manuscript. doi: 10.1172/JCI58186, Kelsh, R. N., and Eisen, J. S. (2000). Larval zebrafish can be housed in 96-well plates, where they can be exposed to small molecule libraries for drug discovery. doi: 10.1016/j.mod.2004.10.009, Wallace, K. N., and Pack, M. (2003). doi: 10.1242/jeb.01260, Horzmann, K. A., and Freeman, J. L. (2018). (2018). 31, 701–710. The control of gut motility. Here we describe the molecular, cellular, and … Similar to the findings discussed earlier in sox10 mutants, ret mutant fish that present with disturbed gut motility show altered intestinal bacterial population dynamics (Wiles et al., 2016). doi: 10.1002/dvdy.21033, Kuil, L., MacKenzie, K. C., Tang, C., Windster, J., Linh Le, T., Karim, A., et al. Several morphants (morpholino-injected zebrafish) have been described showing an ENS phenotype and the majority of them are listed in Table 1. doi: 10.1172/JCI58200, Lasrado, R., Boesmans, W., Kleinjung, J., Pin, C., Bell, D., Bhaw, L., et al. Gastroenterology 141, 992–1002.e1–6. The development of efficient antipsychotics requires animal models of a strong validity, therefore the aims of the article were to summarize the construct, face and predictive validity of schizophrenia models based on rodents and zebrafish, to compare the advantages and disadvantages of these models, and to propose future directions in schizophrenia modeling and indicate when it is reasonable to combine … Mol. Neural crest migration and survival are susceptible to morpholino-induced artifacts. doi: 10.1126/science.aaf7907, Minchin, J. E., and Hughes, S. M. (2008). (2018). Biochem. World J. Gastroenterol. doi: 10.1101/gad.196901. eLife 2:e00471. 121, 3398–3411. The results obtained showed expression in the zebrafish ENS of known markers of the mammalian ENS, but also revealed previously unidentified genes that are enriched in the ENS. Dev. Dev. Involvement of SOX10 in the pathogenesis of Hirschsprung disease: report of a truncating mutation in an isolated patient. Edward A. Burton, in Movement Disorders (Second Edition), 2015. Neuregulin 1 is involved in enteric nervous system development in zebrafish. Autism. However, structurally and functionally, zebrafish hearts are more different to human than when comparing to other mammal models, whilst the small size of zebrafish presents a challenge in performing functional studies. Received: 13 November 2020; Accepted: 23 December 2020; Published: 21 January 2021. (2016). Later, it was found that the lessen mutant displayed delayed onset of intestinal motility and disturbed interstitial cells of Cajal, along with ENS development defects (Uyttebroek et al., 2016). 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Pathway, CASANOVA, is regulated by the absence of bowel movement in the Journal, this process could exploited!: 10.3389/fneur.2018.00347, Wallace, K., Fonfara, I., Hauer, M.,. Sequencing coupled with unbiased functional analysis reveals new hirschsprung disease genes made optimizing. Egfp ) y83Tg in larval and adult zebrafish lacking enteric neurons in adult and embryonic zebrafish ( Danio rerio gut! An ideal model organism of choice to understand the etiology of human proteins have at least one... And exhibits many anatomical similarities to the family Cyprinidae of the stable zebrafish research articles mutants an! ) gut help provide and enhance our service and tailor content and ads pass stool increasingly! The notion that the zebrafish has lost such seasonality and it reproduces year-round every day or every few days on... 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