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Zebrafish: A Powerful Model for Genetics and Genomics 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 24583

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Prof. Dr. Seong-kyu Choe

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Department of Microbiology, School of Medicine, Wonkwang University, Jeonbuk, Republic of Korea
Interests: organelle biology; metabolism; disease models; fatty liver; sarcopenia; adiposity
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Dr. Cheol-Hee Kim

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Guest Editor

Department of Biology, Chungnam National University, Daejeon, Republic of Korea
Interests: developmental genetics; neurogenesis; disease modeling; mental disorders; autism; addiction; schizophrenia
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Dear Colleagues,

Due to the accessibility and generalization of the CRISPR-Cas9 system in any laboratory setting in recent years, there has been tremendous demands on understanding of various diseases at the level of molecular genetics. Zebrafish has evolved as a crucial model organism that has been utilized in almost all fields of biomedical research. In particular, forward genetics performed using zebrafish development has been fruitful to identify the responsible gene, which gives rise distinct phenotypes when functionally abnormal. Now, it is possible to pin out the phenotype in response to a single gene mutation with the discovery of the most advanced ‘reverse-genetics’ tool which becomes much more powerful in a clinical setting when combined with the depth of next-generation sequencing technology.

In this special issue, we invite manuscripts in the format of a research article or a review in the field of zebrafish modeling in genetics and genomics to improve human diseases.

Prof. Dr. Seong-kyu Choe
Dr. Cheol-Hee Kim
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

zebrafish
disease model
reverse genetics
genomics
developmental disorder
gene mutation

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Related Special Issues

Zebrafish: A Powerful Model for Genetics and Genomics 3.0 in International Journal of Molecular Sciences (1 article)
Zebrafish: A Powerful Model for Genetics and Genomics in International Journal of Molecular Sciences (17 articles)

Published Papers (9 papers)

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Research

14 pages, 5694 KiB

Open AccessArticle

Transcriptomics and Phenotypic Analysis of gpr56 Knockout in Zebrafish

by Luning Sun, Boyu Yang, Zheng Peng, Tianle Yang, Bin Qin, Jieyu Ao, Yanqun Yang, Jingling Wang, Lan Zheng and Huaping Xie

Int. J. Mol. Sci. 2023, 24(9), 7740; https://doi.org/10.3390/ijms24097740 - 23 Apr 2023

Cited by 1 | Viewed by 2775

Abstract

The adhesion G-protein-coupled receptor is a seven-transmembrane receptor protein with a complex structure. Impaired GPR56 has been found to cause developmental damage to the human brain, resulting in intellectual disability and motor dysfunction. To date, studies on gpr56 deficiency in zebrafish have been limited to the nervous system, and there have been no reports of its systemic effects on juvenile fish at developmental stages. In order to explore the function of gpr56 in zebrafish, the CRISPR/Cas9 gene-editing system was used to construct a gpr56-knockout zebrafish. Subsequently, the differentially expressed genes (DEGs) at the transcriptional level between the 3 days post fertilization (dpf) homozygotes of the gpr56 mutation and the wildtype zebrafish were analyzed via RNA-seq. The results of the clustering analysis, quantitative PCR (qPCR), and in situ hybridization demonstrated that the expression of innate immunity-related genes in the mutant was disordered, and multiple genes encoding digestive enzymes of the pancreatic exocrine glands were significantly downregulated in the mutant. Motor ability tests demonstrated that the gpr56^−/− zebrafish were more active, and this change was more pronounced in the presence of cold and additional stimuli. In conclusion, our results revealed the effect of gpr56 deletion on the gene expression of juvenile zebrafish and found that the gpr56 mutant was extremely active, providing an important clue for studying the mechanism of gpr56 in the development of juvenile zebrafish. Full article

(This article belongs to the Special Issue Zebrafish: A Powerful Model for Genetics and Genomics 2.0)

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14 pages, 6726 KiB

Open AccessArticle

Transcriptomes of Zebrafish in Early Stages of Multiple Viral Invasions Reveal the Role of Sterols in Innate Immune Switch-On

by Gang Ouyang, Le Yuan, Xiao-Qin Xia, Wanting Zhang and Mijuan Shi

Int. J. Mol. Sci. 2023, 24(5), 4427; https://doi.org/10.3390/ijms24054427 - 23 Feb 2023

Cited by 1 | Viewed by 1577

Abstract

Although it is widely accepted that in the early stages of virus infection, fish pattern recognition receptors are the first to identify viruses and initiate innate immune responses, this process has never been thoroughly investigated. In this study, we infected larval zebrafish with four different viruses and analyzed whole-fish expression profiles from five groups of fish, including controls, at 10 h after infection. At this early stage of virus infection, 60.28% of the differentially expressed genes displayed the same expression pattern across all viruses, with the majority of immune-related genes downregulated and genes associated with protein synthesis and sterol synthesis upregulated. Furthermore, these protein synthesis- and sterol synthesis-related genes were strongly positively correlated in the expression pattern of the rare key upregulated immune genes, IRF3 and IRF7, which were not positively correlated with any known pattern recognition receptor gene. We hypothesize that viral infection triggered a large amount of protein synthesis that stressed the endoplasmic reticulum and the organism responded to this stress by suppressing the body’s immune system while also mediating an increase in steroids. The increase in sterols then participates the activation of IRF3 and IRF7 and triggers the fish’s innate immunological response to the virus infection. Full article

(This article belongs to the Special Issue Zebrafish: A Powerful Model for Genetics and Genomics 2.0)

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13 pages, 2811 KiB

Open AccessArticle

Effects of Nutritionally Induced Obesity on Metabolic Pathways of Zebrafish

by Xixi Li, Guodong Ge, Guili Song, Qing Li and Zongbin Cui

Int. J. Mol. Sci. 2023, 24(3), 1850; https://doi.org/10.3390/ijms24031850 - 17 Jan 2023

Cited by 4 | Viewed by 3703

Abstract

Human obesity has become a global epidemic that can lead to many metabolic diseases, including insulin resistance, type 2 diabetes, dyslipidemia, hypertension and nonalcoholic fatty liver. The development of obesity is closely associated with excess food intake and energy imbalance, family history, lifestyle, psychology and other factors, but molecular mechanisms underlying the induction and development of obesity remain to be intensively studied under a variety of internal and external pathogenesis conditions. In this study, we generated two obesity models of zebrafish that were treated with a high-fat diet (HFD) or an overfeeding diet (DIO). Both HFD and DIO zebrafish exhibited higher levels of lipid accumulation, fat distribution, microvascular steatosis and ectopic accumulation of lipid droplets in liver and muscle than normal diet (NOD) fish. The comparison of transcriptome sequencing data for the livers of HFD, DIO and NOD groups identified common and specific genes and signaling pathways that are potentially associated with zebrafish obesity induced by HFD and/or DIO. These findings provide clues for further understanding the mechanisms of obesity development and preventing nutritionally induced obesity through targeting the common signaling pathways and biological processes. Full article

(This article belongs to the Special Issue Zebrafish: A Powerful Model for Genetics and Genomics 2.0)

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15 pages, 3516 KiB

Open AccessArticle

Predicting Modifiers of Genotype-Phenotype Correlations in Craniofacial Development

by Ranjeet D. Kar and Johann K. Eberhart

Int. J. Mol. Sci. 2023, 24(2), 1222; https://doi.org/10.3390/ijms24021222 - 8 Jan 2023

Cited by 2 | Viewed by 2204

Abstract

Most human birth defects are phenotypically variable even when they share a common genetic basis. Our understanding of the mechanisms of this variation is limited, but they are thought to be due to complex gene-environment interactions. Loss of the transcription factor Gata3 associates with the highly variable human birth defects HDR syndrome and microsomia, and can lead to disruption of the neural crest-derived facial skeleton. We have demonstrated that zebrafish gata3 mutants model the variability seen in humans, with genetic background and candidate pathways modifying the resulting phenotype. In this study, we sought to use an unbiased bioinformatic approach to identify environmental modifiers of gata3 mutant craniofacial phenotypes. The LINCs L1000 dataset identifies chemicals that generate differential gene expression that either positively or negatively correlates with an input gene list. These chemicals are predicted to worsen or lessen the mutant phenotype, respectively. We performed RNA-seq on neural crest cells isolated from zebrafish across control, Gata3 loss-of-function, and Gata3 rescue groups. Differential expression analyses revealed 551 potential targets of gata3. We queried the LINCs database with the 100 most upregulated and 100 most downregulated genes. We tested the top eight available chemicals predicted to worsen the mutant phenotype and the top eight predicted to lessen the phenotype. Of these, we found that vinblastine, a microtubule inhibitor, and clofibric acid, a PPAR-alpha agonist, did indeed worsen the gata3 phenotype. The Topoisomerase II and RNA-pol II inhibitors daunorubicin and triptolide, respectively, lessened the phenotype. GO analysis identified Wnt signaling and RNA polymerase function as being enriched in our RNA-seq data, consistent with the mechanism of action of some of the chemicals. Our study illustrates multiple potential pathways for Gata3 function, and demonstrates a systematic, unbiased process to identify modifiers of genotype-phenotype correlations. Full article

(This article belongs to the Special Issue Zebrafish: A Powerful Model for Genetics and Genomics 2.0)

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17 pages, 3031 KiB

Open AccessArticle

CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene setd5 Leads to Social Impairments in Zebrafish

by Chiara Gabellini, Cecilia Pucci, Chiara De Cesari, Davide Martini, Caterina Di Lauro, Matteo Digregorio, William Norton, Alessio Zippo, Alessandro Sessa, Vania Broccoli and Massimiliano Andreazzoli

Int. J. Mol. Sci. 2023, 24(1), 167; https://doi.org/10.3390/ijms24010167 - 22 Dec 2022

Cited by 5 | Viewed by 3661

Abstract

Haploinsufficiency of the SETD5 gene, encoding a SET domain-containing histone methyltransferase, has been identified as a cause of intellectual disability and Autism Spectrum Disorder (ASD). Recently, the zebrafish has emerged as a valuable model to study neurodevelopmental disorders because of its genetic tractability, robust behavioral traits and amenability to high-throughput drug screening. To model human SETD5 haploinsufficiency, we generated zebrafish setd5 mutants using the CRISPR/Cas9 technology and characterized their morphological, behavioral and molecular phenotypes. According to our observation that setd5 is expressed in adult zebrafish brain, including those areas controlling social behavior, we found that setd5 heterozygous mutants exhibit defective aggregation and coordination abilities required for shoaling interactions, as well as indifference to social stimuli. Interestingly, impairment in social interest is rescued by risperidone, an antipsychotic drug used to treat behavioral traits in ASD individuals. The molecular analysis underscored the downregulation of genes encoding proteins involved in the synaptic structure and function in the adult brain, thus suggesting that brain hypo-connectivity could be responsible for the social impairments of setd5 mutant fishes. The zebrafish setd5 mutants display ASD-like features and are a promising setd5 haploinsufficiency model for drug screening aimed at reversing the behavioral phenotypes. Full article

(This article belongs to the Special Issue Zebrafish: A Powerful Model for Genetics and Genomics 2.0)

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9 pages, 6212 KiB

Open AccessArticle

Evaluation of a Rapid and Simple Method for Assessing Retinal Vessel Structures in Adult Zebrafish

by Yu-Ri Lee, Myeongjoo Son, Young Sook Kim, Jin Sook Kim, Cheol-Hee Kim and Seung-Hyun Jung

Int. J. Mol. Sci. 2022, 23(23), 15069; https://doi.org/10.3390/ijms232315069 - 1 Dec 2022

Cited by 3 | Viewed by 2015

Abstract

The evaluation of retinal vascular structures is important for analyzing various ophthalmic diseases. Conventional trypsin digestion was used for separating retinal vasculatures in mouse, rat, and other animal models; however, the trypsin method alone is technically difficult to perform and has not been reported in zebrafish to date. In this study, we introduced a rapid and convenient method that allows the investigation of fine vessel structures at a cellular level in the relatively intact retinal vasculature of adult zebrafish. Using an anti-ZO-1 antibody, tight junction structures in retinal vessels were examined in detail and several different cell types constituting blood vessels in arterial and capillary areas were identified. In addition, using cell type-specific antibodies, we identified smooth muscle cells, blood cells, and endothelial cells in the retinal vasculature. Finally, using the hyperglycemic model, we observed the dilation of retinal vessels, the downregulation of tight junction proteins, and the reduction in smooth muscle cells. Based on these results, we provide a rapid and convenient method for the study of retinal vasculature disease in the zebrafish animal model. Full article

(This article belongs to the Special Issue Zebrafish: A Powerful Model for Genetics and Genomics 2.0)

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16 pages, 2106 KiB

Open AccessArticle

Requirement of Zebrafish Adcy3a and Adcy5 in Melanosome Dispersion and Melanocyte Stripe Formation

by Lin Zhang, Meng Wan, Ramila Tohti, Daqing Jin and Tao P. Zhong

Int. J. Mol. Sci. 2022, 23(22), 14182; https://doi.org/10.3390/ijms232214182 - 16 Nov 2022

Cited by 5 | Viewed by 2387

Abstract

cAMP-PKA signaling plays a pivotal role in melanin synthesis and melanosome transport by responding to the binding of the α-melanocyte-stimulating hormone (α-MSH) to melanocortin-1 receptor (MC1R). Adenylate cyclases (ADCYs) are the enzymes responsible for the synthesis of cAMP from ATP, which comprises nine transmembrane isoforms (ADCYs 1-9) and one soluble adenylate cyclase (ADCY 10) in mammals. However, little is known about which and how ADCY isoforms regulate melanocyte generation, melanin biosynthesis, and melanosome transport in vivo. In this study, we have generated a series of single and double mutants of Adcy isoforms in zebrafish. Among them, adcy3a^-/- and adcy5^-/- double mutants cause defects in melanosome dispersion but do not impair melanoblast differentiation and melanocyte regeneration during the embryonic or larval stages. Activation of PKA, the main effector of cAMP signaling, significantly ameliorates the defects in melanosome dispersion in adcy3a^-/- and adcy5^-/- double mutants. Mechanistically, Adcy3a and Adcy5 regulate melanosome dispersion by activating kinesin-1 while inhibiting cytoplasmic dynein-1. In adult zebrafish, Adcy3a and Adcy5 participate in the regulation of the expression of microphthalmia transcription factor (Mitfa) and melanin synthesis enzymes Tyr, Dct, and Trp1b. The deletion of Adcy3a and Adcy5 inhibits melanin production and reduces pigmented melanocyte numbers, causing a defect in establishing adult melanocyte stripes. Hence, our studies demonstrate that Adcy3a and Adcy5 play essential but redundant functions in mediating α-MSH-MC1R/cAMP-PKA signaling for regulating melanin synthesis and melanosome dispersion. Full article

(This article belongs to the Special Issue Zebrafish: A Powerful Model for Genetics and Genomics 2.0)

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22 pages, 4957 KiB

Open AccessArticle

Understanding the Function and Mechanism of Zebrafish Tmem39b in Regulating Cold Resistance

by Renyan Liu, Yong Long, Ran Liu, Guili Song, Qing Li, Huawei Yan and Zongbin Cui

Int. J. Mol. Sci. 2022, 23(19), 11442; https://doi.org/10.3390/ijms231911442 - 28 Sep 2022

Cited by 8 | Viewed by 2323

Abstract

Autophagy and endoplasmic reticulum (ER) stress response are among the key pathways regulating cold resistance of fish through eliminating damaged cellular components and facilitating the restoration of cell homeostasis upon exposure to acute cold stress. The transmembrane protein 39A (TMEM39A) was reported to regulate both autophagy and ER stress response, but its vertebrate-specific paralog, the transmembrane protein 39B (TMEM39B), has not been characterized. In the current study, we generate tmem39b-knockout zebrafish lines and characterize their survival ability under acute cold stress. We observed that the dysfunction of Tmem39b remarkably decreased the cold resilience of both the larval and adult zebrafish. Gene transcription in the larvae exposed to cold stress and rewarming were characterized by RNA sequencing (RNA-seq) to explore the mechanisms underlying functions of Tmem39b in regulating cold resistance. The results indicate that the deficiency of Tmem39b attenuates the up-regulation of both cold- and rewarming-induced genes. The cold-induced transcription factor genes bif1.2, fosab, and egr1, and the rewarming-activated immune genes c3a.3, il11a, and sting1 are the representatives influenced by Tmem39b dysfunction. However, the loss of tmem39b has little effect on the transcription of the ER stress response- and autophagy-related genes. The measurements of the phosphorylated H2A histone family member X (at Ser 139, abbreviated as γH2AX) demonstrate that zebrafish Tmem39b protects the cells against DNA damage caused by exposure to the cold-warming stress and facilitates tissue damage repair during the recovery phase. The gene modules underlying the functions of Tmem39b in zebrafish are highly enriched in biological processes associated with immune response. The dysfunction of Tmem39b also attenuates the up-regulation of tissue C-reactive protein (CRP) content upon rewarming. Together, our data shed new light on the function and mechanism of Tmem39b in regulating the cold resistance of fish. Full article

(This article belongs to the Special Issue Zebrafish: A Powerful Model for Genetics and Genomics 2.0)

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14 pages, 5126 KiB

Open AccessArticle

Phylogenetic and Expression Analysis of Fos Transcription Factors in Zebrafish

by Khadizatul Kubra, Gurveer K. Gaddu, Clifford Liongue, Somayyeh Heidary, Alister C. Ward, Amardeep S. Dhillon and Faiza Basheer

Int. J. Mol. Sci. 2022, 23(17), 10098; https://doi.org/10.3390/ijms231710098 - 3 Sep 2022

Cited by 3 | Viewed by 3008

Abstract

Members of the FOS protein family regulate gene expression responses to a multitude of extracellular signals and are dysregulated in several pathological states. Whilst mouse genetic models have provided key insights into the tissue-specific functions of these proteins in vivo, little is known about their roles during early vertebrate embryonic development. This study examined the potential of using zebrafish as a model for such studies and, more broadly, for investigating the mechanisms regulating the functions of Fos proteins in vivo. Through phylogenetic and sequence analysis, we identified six zebrafish FOS orthologues, fosaa, fosab, fosb, fosl1a, fosl1b, and fosl2, which show high conservation in key regulatory domains and post-translational modification sites compared to their equivalent human proteins. During embryogenesis, zebrafish fos genes exhibit both overlapping and distinct spatiotemporal patterns of expression in specific cell types and tissues. Most fos genes are also expressed in a variety of adult zebrafish tissues. As in humans, we also found that expression of zebrafish FOS orthologs is induced by oncogenic BRAF-ERK signalling in zebrafish melanomas. These findings suggest that zebrafish represent an alternate model to mice for investigating the regulation and functions of Fos proteins in vertebrate embryonic and adult tissues, and cancer. Full article

(This article belongs to the Special Issue Zebrafish: A Powerful Model for Genetics and Genomics 2.0)

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