Biomedicines

Editorial

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3 pages, 155 KiB

Open AccessEditorial

Another Swim in the Extensive Pool of Zebrafish Research

by James A. Marrs and Swapnalee Sarmah

Biomedicines 2024, 12(3), 546; https://doi.org/10.3390/biomedicines12030546 - 29 Feb 2024

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Abstract

The zebrafish has gained utility in modeling biomedical phenomena for discovery research [...] Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

Research

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10 pages, 3585 KiB

Open AccessArticle

Cutaneous and Developmental Effects of CARD14 Overexpression in Zebrafish

by Avital Baniel, Limor Ziv, Zohar Ben-Moshe, Ofer Sarig, Janan Mohamad, Alon Peled, Gideon Rechavi, Yoav Gothilf and Eli Sprecher

Biomedicines 2022, 10(12), 3192; https://doi.org/10.3390/biomedicines10123192 - 8 Dec 2022

Viewed by 1698

Abstract

Background: Gain-of-function mutations in CARD14 have recently been shown to be involved in the pathogenesis of psoriasis and pityriasis rubra pilaris (PRP). Those mutations were found to activate the NF-kB signaling pathway. Objective: Zebrafish is often used to model human diseases in general, [...] Read more.

Background: Gain-of-function mutations in CARD14 have recently been shown to be involved in the pathogenesis of psoriasis and pityriasis rubra pilaris (PRP). Those mutations were found to activate the NF-kB signaling pathway. Objective: Zebrafish is often used to model human diseases in general, and in skin disorders more particularly. In the present study, we aimed to examine the effect of CARD14 overexpression in zebrafish with the aim to validate this model for future translational applications. Methods: We used light microscopy, scanning electron microscopy, histological analysis and whole mount in situ hybridization as well as real-time PCR to ascertain the effect of CARD14 overexpression in the developing zebrafish. Results: Overexpression of human CARD14 had a marked morphological and developmental effect on the embryos. Light microscopy demonstrated a characteristic cutaneous pattern including a granular surface and a spiky pigment pattern. In situ hybridization revealed keratinocytes of uneven size and shape. Scanning electron microscopy showed aberrant production of actin microridges and a rugged keratinocyte cell surface, reminiscent of the human hyperkeratotic phenotype. Developmentally, overexpression of CARD14 had a variable effect on anterior-posterior axis symmetry. Similar to what has been observed in humans with psoriasis or PRP, NF-kB expression was higher in CARD14-overexpressing embryos compared to controls. Conclusions: Overexpression of CARD14 results in a distinct cutaneous pattern accompanied by hyperactivation of the NF-kB pathway, suggesting that the zebrafish represents a useful system to model CARD14-associated papulosquamous diseases. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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21 pages, 3243 KiB

Open AccessArticle

Acute Administration of Ethanol and of a D1-Receptor Antagonist Affects the Behavior and Neurochemistry of Adult Zebrafish

by Tanya Scerbina and Robert Gerlai

Biomedicines 2022, 10(11), 2878; https://doi.org/10.3390/biomedicines10112878 - 10 Nov 2022

Cited by 1 | Viewed by 1912

Abstract

Alcohol abuse represents major societal problems, an unmet medical need resulting from our incomplete understanding of the mechanisms underlying alcohol’s actions in the brain. To uncover these mechanisms, animal models have been proposed. Here, we explore the effects of acute alcohol administration in [...] Read more.

Alcohol abuse represents major societal problems, an unmet medical need resulting from our incomplete understanding of the mechanisms underlying alcohol’s actions in the brain. To uncover these mechanisms, animal models have been proposed. Here, we explore the effects of acute alcohol administration in zebrafish, a promising animal model in alcohol research. One mechanism via which alcohol may influence behavior is the dopaminergic neurotransmitter system. As a proof-of-concept analysis, we study how D1 dopamine-receptor antagonism may alter the effects of acute alcohol on the behavior of adult zebrafish and on whole brain levels of neurochemicals. We conduct these analyses using a quasi-inbred strain, AB, and a genetically heterogeneous population SFWT. Our results uncover significant alcohol x D1-R antagonist interaction and main effects of these factors in shoaling, but only additive effects of these factors in measures of exploratory behavior. We also find interacting and main effects of alcohol and the D1-R antagonist on dopamine and DOPAC levels, but only alcohol effects on serotonin. We also uncover several strain dependent effects. These results demonstrate that acute alcohol may act through dopaminergic mechanisms for some but not all behavioral phenotypes, a novel discovery, and also suggest that strain differences may, in the future, help us identify molecular mechanisms underlying acute alcohol effects. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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21 pages, 3483 KiB

Open AccessEditor’s ChoiceArticle

osr1 Maintains Renal Progenitors and Regulates Podocyte Development by Promoting wnt2ba via the Antagonism of hand2

by Bridgette E. Drummond, Brooke E. Chambers, Hannah M. Wesselman, Shannon Gibson, Liana Arceri, Marisa N. Ulrich, Gary F. Gerlach, Paul T. Kroeger, Ignaty Leshchiner, Wolfram Goessling and Rebecca A. Wingert

Biomedicines 2022, 10(11), 2868; https://doi.org/10.3390/biomedicines10112868 - 9 Nov 2022

Cited by 11 | Viewed by 2895

Abstract

Knowledge about the genetic pathways that control nephron development is essential for better understanding the basis of congenital malformations of the kidney. The transcription factors Osr1 and Hand2 are known to exert antagonistic influences to balance kidney specification. Here, we performed a forward [...] Read more.

Knowledge about the genetic pathways that control nephron development is essential for better understanding the basis of congenital malformations of the kidney. The transcription factors Osr1 and Hand2 are known to exert antagonistic influences to balance kidney specification. Here, we performed a forward genetic screen to identify nephrogenesis regulators, where whole genome sequencing identified an osr1 lesion in the novel oceanside (ocn) mutant. The characterization of the mutant revealed that osr1 is needed to specify not renal progenitors but rather their maintenance. Additionally, osr1 promotes the expression of wnt2ba in the intermediate mesoderm (IM) and later the podocyte lineage. wnt2ba deficiency reduced podocytes, where overexpression of wnt2ba was sufficient to rescue podocytes and osr1 deficiency. Antagonism between osr1 and hand2 mediates podocyte development specifically by controlling wnt2ba expression. These studies reveal new insights about the roles of Osr1 in promoting renal progenitor survival and lineage choice. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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18 pages, 4039 KiB

Open AccessArticle

Comparative Transcriptome Analysis Provides Novel Molecular Events for the Differentiation and Maturation of Hepatocytes during the Liver Development of Zebrafish

by Yasong Zhao, Xiaohui Li, Guili Song, Qing Li, Huawei Yan and Zongbin Cui

Biomedicines 2022, 10(9), 2264; https://doi.org/10.3390/biomedicines10092264 - 13 Sep 2022

Viewed by 2533

Abstract

The liver plays an essential role in multiple biological functions including metabolism, detoxification, digestion, coagulation, and homeostasis in vertebrates. The specification and differentiation of embryonic hepatoblasts, the proliferation of hepatocytes, and the hepatic tissue architecture are well documented, but molecular events governing the [...] Read more.

The liver plays an essential role in multiple biological functions including metabolism, detoxification, digestion, coagulation, and homeostasis in vertebrates. The specification and differentiation of embryonic hepatoblasts, the proliferation of hepatocytes, and the hepatic tissue architecture are well documented, but molecular events governing the maturation of hepatocytes during liver development remain largely unclear. In this study, we performed a comparative transcriptome analysis of hepatocytes that were sorted by flow cytometry from developing zebrafish embryos at 60, 72, and 96 hpf. We identified 667 up-regulated and 3640 down-regulated genes in hepatocytes between 60 and 72 hpf, 606 up-regulated and 3924 down-regulated genes between 60 and 96 hpf, and 1693 up-regulated genes and 1508 down-regulated genes between 72 and 96 hpf. GO enrichment analysis revealed that key biological processes, cellular components, and molecular functions in hepatocytes between 60 to 72 hpf, such as cell cycle, DNA replication, DNA repair, RNA processing, and transcription regulation, are mainly associated with the proliferation of hepatocytes. In addition to biological processes, cellular components, and molecular functions for cell proliferation, molecular functions for carbohydrate metabolism were enriched in hepatocytes during 72 to 96 hpf. KEGG enrichment analysis identified key signaling pathways, such as cell cycle, RNA degradation, ubiquitin-mediated proteolysis, ErbB and Hedgehog signaling, basal transcription factors, Wnt signaling, and glycan degradation, which are closely associated with cell proliferation or carbohydrate metabolism in hepatocytes between 60 to 72 hpf. Newly enriched signaling pathways in hepatocytes during 72 to 96 hpf include metabolisms of pyrimidine, purine, nicotinate and nicotinamide, caffeine, glycine, serine and threonine, ABC transporters, and p53 signaling that function in metabolisms of lipid, protein and energy, cellular secretion, or detoxification, indicating the functional maturation of hepatocytes between 72 to 96 hpf. These findings provide novel clues for further understanding the functional differentiation and maturation of hepatocytes during liver development. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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13 pages, 2407 KiB

Open AccessArticle

Zebrafish: A Useful Animal Model for the Characterization of Drug-Loaded Polymeric NPs

by Sara Bozzer, Luca De Maso, Maria Cristina Grimaldi, Sara Capolla, Michele Dal Bo, Giuseppe Toffoli and Paolo Macor

Biomedicines 2022, 10(9), 2252; https://doi.org/10.3390/biomedicines10092252 - 11 Sep 2022

Cited by 4 | Viewed by 1969

Abstract

The use of zebrafish (ZF) embryos as an in vivo model is increasingly attractive thanks to different features that include easy handling, transparency, and the absence of adaptive immunity until 4–6 weeks. These factors allow the development of xenografts that can be easily [...] Read more.

The use of zebrafish (ZF) embryos as an in vivo model is increasingly attractive thanks to different features that include easy handling, transparency, and the absence of adaptive immunity until 4–6 weeks. These factors allow the development of xenografts that can be easily analyzed through fluorescence techniques. In this work, ZF were exploited to characterize the efficiency of drug-loaded polymeric NPs as a therapeutical approach for B-cell malignancies. Fluorescent probes, fluorescent transgenic lines of ZF, or their combination allowed to deeply examine biodistribution, elimination, and therapeutic efficacy. In particular, the fluorescent signal of nanoparticles (NPs) was exploited to investigate the in vivo distribution, while the colocalization between the fluorescence in macrophages and NPs allows following the elimination pathway of these polymeric NPs. Xenotransplanted human B-cells (Nalm-6) developed a reproducible model useful for demonstrating drug delivery by polymeric NPs loaded with doxorubicin and, as a consequence, the arrest of tumor growth and the reduction in tumor burden. ZF proved to be a versatile model, able to rapidly provide answers in the development of animal models and in the characterization of the activity and the efficacy of drug delivery systems. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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18 pages, 4872 KiB

Open AccessArticle

Effect of Lipopolysaccharides on Liver Tumor Metastasis of twist1a/kras^V12 Double Transgenic Zebrafish

by Jeng-Wei Lu, Liang-In Lin, Yuxi Sun, Dong Liu and Zhiyuan Gong

Biomedicines 2022, 10(1), 95; https://doi.org/10.3390/biomedicines10010095 - 2 Jan 2022

Cited by 2 | Viewed by 2591

Abstract

The poor prognosis of patients diagnosed with hepatocellular carcinoma (HCC) is directly associated with the multi-step process of tumor metastasis. TWIST1, a basic helix-loop-helix (bHLH) transcription factor, is the most important epithelial-mesenchymal transition (EMT) gene involved in embryonic development, tumor progression, and [...] Read more.

The poor prognosis of patients diagnosed with hepatocellular carcinoma (HCC) is directly associated with the multi-step process of tumor metastasis. TWIST1, a basic helix-loop-helix (bHLH) transcription factor, is the most important epithelial-mesenchymal transition (EMT) gene involved in embryonic development, tumor progression, and metastasis. However, the role that TWIST1 gene plays in the process of liver tumor metastasis in vivo is still not well understood. Zebrafish can serve as a powerful model for cancer research. Thus, in this study, we crossed twist1a+ and kras+ transgenic zebrafish, which, respectively, express hepatocyte-specific mCherry and enhanced green fluorescent protein (EGFP); they also drive overexpression of their respective transcription factors. This was found to exacerbate the development of metastatic HCC. Fluorescence of mCherry and EGFP-labeled hepatocytes revealed that approximately 37.5% to 45.5% of the twist1a+/kras+ double transgenic zebrafish exhibited spontaneous tumor metastasis from the liver to the abdomen and tail areas, respectively. We also investigated the inflammatory effects of lipopolysaccharides (LPS) on the hepatocyte-specific co-expression of twist1a+ and kras+ in double transgenic zebrafish. Following LPS exposure, co-expression of twist1a+ and kras+ was found to increase tumor metastasis by 57.8%, likely due to crosstalk with the EMT pathway. Our results confirm that twist1a and kras are important mediators in the development of metastatic HCC. Taken together, our in-vivo model demonstrated that co-expression of twist1a+/kras+ in conjunction with exposure to LPS enhanced metastatic HCC offers a useful platform for the study of tumor initiation and metastasis in liver cancer. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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13 pages, 2304 KiB

Open AccessArticle

An Orthotopic Model of Uveal Melanoma in Zebrafish Embryo: A Novel Platform for Drug Evaluation

by Chiara Tobia, Daniela Coltrini, Roberto Ronca, Alessandra Loda, Jessica Guerra, Elisa Scalvini, Francesco Semeraro and Sara Rezzola

Biomedicines 2021, 9(12), 1873; https://doi.org/10.3390/biomedicines9121873 - 10 Dec 2021

Cited by 5 | Viewed by 3029

Abstract

Uveal melanoma is a highly metastatic tumor, representing the most common primary intraocular malignancy in adults. Tumor cell xenografts in zebrafish embryos may provide the opportunity to study in vivo different aspects of the neoplastic disease and its response to therapy. Here, we [...] Read more.

Uveal melanoma is a highly metastatic tumor, representing the most common primary intraocular malignancy in adults. Tumor cell xenografts in zebrafish embryos may provide the opportunity to study in vivo different aspects of the neoplastic disease and its response to therapy. Here, we established an orthotopic model of uveal melanoma in zebrafish by injecting highly metastatic murine B16-BL6 and B16-LS9 melanoma cells, human A375M melanoma cells, and human 92.1 uveal melanoma cells into the eye of zebrafish embryos in the proximity of the developing choroidal vasculature. Immunohistochemical and immunofluorescence analyses showed that melanoma cells proliferate during the first four days after injection and move towards the eye surface. Moreover, bioluminescence analysis of luciferase-expressing human 92.1 uveal melanoma cells allowed the quantitative assessment of the antitumor activity exerted by the canonical chemotherapeutic drugs paclitaxel, panobinostat, and everolimus after their injection into the grafted eye. Altogether, our data demonstrate that the zebrafish embryo eye is a permissive environment for the growth of invasive cutaneous and uveal melanoma cells. In addition, we have established a new luciferase-based in vivo orthotopic model that allows the quantification of human uveal melanoma cells engrafted in the zebrafish embryo eye, and which may represent a suitable tool for the screening of novel drug candidates for uveal melanoma therapy. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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21 pages, 5557 KiB

Open AccessArticle

Knockout of mafba Causes Inner-Ear Developmental Defects in Zebrafish via the Impairment of Proliferation and Differentiation of Ionocyte Progenitor Cells

by Xiang Chen, Yuwen Huang, Pan Gao, Yuexia Lv, Danna Jia, Kui Sun, Yunqiao Han, Hualei Hu, Zhaohui Tang, Xiang Ren and Mugen Liu

Biomedicines 2021, 9(11), 1699; https://doi.org/10.3390/biomedicines9111699 - 16 Nov 2021

Cited by 3 | Viewed by 2869

Abstract

Zebrafish is an excellent model for exploring the development of the inner ear. Its inner ear has similar functions to that of humans, specifically in the maintenance of hearing and balance. Mafba is a component of the Maf transcription factor family. It participates [...] Read more.

Zebrafish is an excellent model for exploring the development of the inner ear. Its inner ear has similar functions to that of humans, specifically in the maintenance of hearing and balance. Mafba is a component of the Maf transcription factor family. It participates in multiple biological processes, but its role in inner-ear development remains poorly understood. In this study, we constructed a mafba knockout (mafba^−/−) zebrafish model using CRISPR/Cas9 technology. The mafba^−/− mutant inner ear displayed severe impairments, such as enlarged otocysts, smaller or absent otoliths, and insensitivity to sound stimulation. The proliferation of p63⁺ epidermal stem cells and dlc⁺ ionocyte progenitors was inhibited in mafba^−/− mutants. Moreover, the results showed that mafba deletion induces the apoptosis of differentiated K⁺-ATPase-rich (NR) cells and H⁺-ATPase-rich (HR) cells. The activation of p53 apoptosis and G0/G1 cell cycle arrest resulted from DNA damage in the inner-ear region, providing a mechanism to account for the inner ear deficiencies. The loss of homeostasis resulting from disorders of ionocyte progenitors resulted in structural defects in the inner ear and, consequently, loss of hearing. In conclusion, the present study elucidated the function of ionic channel homeostasis and inner-ear development using a zebrafish Mafba model and clarified the possible physiological roles. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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13 pages, 3290 KiB

Open AccessArticle

Functions of SMC2 in the Development of Zebrafish Liver

by Xixi Li, Guili Song, Yasong Zhao, Jing Ren, Qing Li and Zongbin Cui

Biomedicines 2021, 9(9), 1240; https://doi.org/10.3390/biomedicines9091240 - 16 Sep 2021

Cited by 4 | Viewed by 2882

Abstract

SMC2 (structural maintenance of chromosomes 2) is the core subunit of condensins, which play a central role in chromosome organization and segregation. However, the functions of SMC2 in embryonic development remain poorly understood, due to the embryonic lethality of homozygous SMC2^−/− mice. [...] Read more.

SMC2 (structural maintenance of chromosomes 2) is the core subunit of condensins, which play a central role in chromosome organization and segregation. However, the functions of SMC2 in embryonic development remain poorly understood, due to the embryonic lethality of homozygous SMC2^−/− mice. Herein, we explored the roles of SMC2 in the liver development of zebrafish. The depletion of SMC2, with the CRISPR/Cas9-dependent gene knockout approach, led to a small liver phenotype. The specification of hepatoblasts was unaffected. Mechanistically, extensive apoptosis occurred in the liver of SMC2 mutants, which was mainly associated with the activation of the p53-dependent apoptotic pathway. Moreover, an aberrant activation of a series of apoptotic pathways in SMC2 mutants was involved in the defective chromosome segregation and subsequent DNA damage. Therefore, our findings demonstrate that SMC2 is necessary for zebrafish liver development. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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23 pages, 7586 KiB

Open AccessArticle

Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of kras^V¹² in Transgenic Zebrafish

by Jeng-Wei Lu, Yuxi Sun, Pei-Shi Angelina Fong, Liang-In Lin, Dong Liu and Zhiyuan Gong

Biomedicines 2021, 9(8), 974; https://doi.org/10.3390/biomedicines9080974 - 7 Aug 2021

Cited by 5 | Viewed by 3013

Abstract

Intestinal carcinogenesis is a multistep process that begins with epithelial hyperplasia, followed by a transition to an adenoma and then to a carcinoma. Many etiological factors, including KRAS mutations and inflammation, have been implicated in oncogenesis. However, the potential synergistic effects between KRAS [...] Read more.

Intestinal carcinogenesis is a multistep process that begins with epithelial hyperplasia, followed by a transition to an adenoma and then to a carcinoma. Many etiological factors, including KRAS mutations and inflammation, have been implicated in oncogenesis. However, the potential synergistic effects between KRAS mutations and inflammation as well as the potential mechanisms by which they promote intestinal carcinogenesis remain unclear. Thus, the objective of this study was to investigate the synergistic effects of kras^V¹², lipopolysaccharides (LPS), and/or dextran sulfate sodium (DSS) on inflammation, tumor progression, and intestinal disorders using transgenic adults and larvae of zebrafish. Histopathology and pathological staining were used to examine the intestines of kras^V¹² transgenic zebrafish treated with LPS and/or DSS. LPS and/or DSS treatment enhanced intestinal inflammation in kras^V¹² transgenic larvae with concomitant increases in the number of neutrophils and macrophages in the intestines. The expression of kras^V¹², combined with LPS treatment, also enhanced epithelial hyperplasia and tubular adenoma, demonstrated by histopathological examinations and by increases in cell apoptosis, cell proliferation, and downstream signaling of phosphorylated AKT serine/threonine kinase 1 (AKT), extracellular-signal-regulated kinase (ERK), and histone. We also found that kras^V¹² expression, combined with LPS treatment, significantly enhanced changes in intestinal morphology, specifically (1) decreases in goblet cell number, goblet cell size, villi height, and intervilli space, as well as (2) increases in villi width and smooth muscle thickness. Moreover, kras^V¹² transgenic larvae cotreated with DSS and LPS exhibited exacerbated intestinal inflammation. Cotreatment with DSS and LPS in kras^V¹²-expressing transgenic adult zebrafish also enhanced epithelial hyperplasia and tubular adenoma, compared with wild-type fish that received the same cotreatment. In conclusion, our data suggest that kras^V¹² expression, combined with LPS and/or DSS treatment, can enhance intestinal tumor progression by activating the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway and may provide a valuable in vivo platform to investigate tumor initiation and antitumor drugs for gastrointestinal cancers. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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18 pages, 3743 KiB

Open AccessArticle

Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish

by Yang-Wen Hsieh, Yi-Wen Tsai, Hsin-Hung Lai, Chi-Yu Lai, Chiu-Ya Lin and Guor Mour Her

Biomedicines 2021, 9(8), 941; https://doi.org/10.3390/biomedicines9080941 - 2 Aug 2021

Cited by 9 | Viewed by 4233

Abstract

The functions of anorexigenic neurons secreting proopiomelanocortin (POMC)/alpha-melanocyte-stimulating hormone (α-MSH) of the melanocortin system in the hypothalamus in vertebrates are energy homeostasis, food intake, and body weight regulation. However, the mechanisms remain elusive. This article reports on zebrafish that have been genetically engineered [...] Read more.

The functions of anorexigenic neurons secreting proopiomelanocortin (POMC)/alpha-melanocyte-stimulating hormone (α-MSH) of the melanocortin system in the hypothalamus in vertebrates are energy homeostasis, food intake, and body weight regulation. However, the mechanisms remain elusive. This article reports on zebrafish that have been genetically engineered to produce α-MSH mutants, α-MSH^−7aa and α-MSH^−8aa, selectively lacking 7 and 8 amino acids within the α-MSH region, but retaining most of the other normal melanocortin-signaling (Pomc-derived) peptides. The α-MSH mutants exhibited hyperphagic phenotypes leading to body weight gain, as observed in human patients and mammalian models. The actions of several genes regulating appetite in zebrafish are similar to those in mammals when analyzed using gene expression analysis. These include four selected orexigenic genes: Promelanin-concentrating hormone (pmch), agouti-related protein 2 (agrp2), neuropeptide Y (npy), and hypothalamic hypocretin/orexin (hcrt). We also study five selected anorexigenic genes: Brain-derived neurotrophic factor (bdnf), single-minded homolog 1-a (sim1a), corticotropin-releasing hormone b (crhb), thyrotropin-releasing hormone (trh), and prohormone convertase 2 (pcsk2). The orexigenic actions of α-MSH mutants are rescued completely after hindbrain ventricle injection with a synthetic analog of α-MSH and a melanocortin receptor agonist, Melanotan II. We evaluate the adverse effects of MSH depletion on energy balance using the Alamar Blue metabolic rate assay. Our results show that α-MSH is a key regulator of POMC signaling in appetite regulation and energy expenditure, suggesting that it might be a potential therapeutic target for treating human obesity. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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34 pages, 14165 KiB

Open AccessArticle

Zebrafish Blunt-Force TBI Induces Heterogenous Injury Pathologies That Mimic Human TBI and Responds with Sonic Hedgehog-Dependent Cell Proliferation across the Neuroaxis

by James Hentig, Kaylee Cloghessy, Manuela Lahne, Yoo Jin Jung, Rebecca A. Petersen, Ann C. Morris and David R. Hyde

Biomedicines 2021, 9(8), 861; https://doi.org/10.3390/biomedicines9080861 - 22 Jul 2021

Cited by 14 | Viewed by 4751

Abstract

Blunt-force traumatic brain injury (TBI) affects an increasing number of people worldwide as the range of injury severity and heterogeneity of injury pathologies have been recognized. Most current damage models utilize non-regenerative organisms, less common TBI mechanisms (penetrating, chemical, blast), and are limited [...] Read more.

Blunt-force traumatic brain injury (TBI) affects an increasing number of people worldwide as the range of injury severity and heterogeneity of injury pathologies have been recognized. Most current damage models utilize non-regenerative organisms, less common TBI mechanisms (penetrating, chemical, blast), and are limited in scalability of injury severity. We describe a scalable blunt-force TBI model that exhibits a wide range of human clinical pathologies and allows for the study of both injury pathology/progression and mechanisms of regenerative recovery. We modified the Marmarou weight drop model for adult zebrafish, which delivers a scalable injury spanning mild, moderate, and severe phenotypes. Following injury, zebrafish display a wide range of severity-dependent, injury-induced pathologies, including seizures, blood–brain barrier disruption, neuroinflammation, edema, vascular injury, decreased recovery rate, neuronal cell death, sensorimotor difficulties, and cognitive deficits. Injury-induced pathologies rapidly dissipate 4–7 days post-injury as robust cell proliferation is observed across the neuroaxis. In the cerebellum, proliferating nestin:GFP-positive cells originated from the cerebellar crest by 60 h post-injury, which then infiltrated into the granule cell layer and differentiated into neurons. Shh pathway genes increased in expression shortly following injury. Injection of the Shh agonist purmorphamine in undamaged fish induced a significant proliferative response, while the proliferative response was inhibited in injured fish treated with cyclopamine, a Shh antagonist. Collectively, these data demonstrate that a scalable blunt-force TBI to adult zebrafish results in many pathologies similar to human TBI, followed by recovery, and neuronal regeneration in a Shh-dependent manner. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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Review

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11 pages, 640 KiB

Open AccessReview

Ethanol Effects on Early Developmental Stages Studied Using the Zebrafish

by Priyadharshini Manikandan, Swapnalee Sarmah and James A. Marrs

Biomedicines 2022, 10(10), 2555; https://doi.org/10.3390/biomedicines10102555 - 13 Oct 2022

Cited by 4 | Viewed by 3409

Abstract

Fetal alcohol spectrum disorder (FASD) results from prenatal ethanol exposure. The zebrafish (Danio rerio) is an outstanding in vivo FASD model. Early development produced the three germ layers and embryonic axes patterning. A critical pluripotency transcriptional gene circuit of sox2, [...] Read more.

Fetal alcohol spectrum disorder (FASD) results from prenatal ethanol exposure. The zebrafish (Danio rerio) is an outstanding in vivo FASD model. Early development produced the three germ layers and embryonic axes patterning. A critical pluripotency transcriptional gene circuit of sox2, pou5f1 (oct4; recently renamed pou5f3), and nanog maintain potency and self-renewal. Ethanol affects sox2 expression, which functions with pou5f1 to control target gene transcription. Various genes, like elf3, may interact and regulate sox2, and elf3 knockdown affects early development. Downstream of the pluripotency transcriptional circuit, developmental signaling activities regulate morphogenetic cell movements and lineage specification. These activities are also affected by ethanol exposure. Hedgehog signaling is a critical developmental signaling pathway that controls numerous developmental events, including neural axis specification. Sonic hedgehog activities are affected by embryonic ethanol exposure. Activation of sonic hedgehog expression is controlled by TGF-ß family members, Nodal and Bmp, during dorsoventral (DV) embryonic axis establishment. Ethanol may perturb TGF-ß family receptors and signaling activities, including the sonic hedgehog pathway. Significantly, experiments show that activation of sonic hedgehog signaling rescues some embryonic ethanol exposure effects. More research is needed to understand how ethanol affects early developmental signaling and morphogenesis. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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