Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis

Sun, Jie; She, Peilu; Liu, Xu; Gao, Bangjun; Jin, Daqin; Zhong, Tao

doi:10.3390/ijms22010278

Cited by 20 publications

(32 citation statements)

References 52 publications

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“…Using a CRISPR/Cas9-based methodology we were able to create frameshift mutations in both functional zebrafish ABCC6 paralogs, abcc6a, and abcc6b.1. The phenotypic analysis of single and double mutants, both at larval and adult stages suggested that whereas abcc6a has major roles in mineralization, as has been suggested by previous studies (Mackay et al, 2015;Van Gils et al, 2018;Sun et al, 2021), abcc6b.1 appears to be dispensable for this process under normal conditions. In the absence of Abcc6a function we observe precocious mineralization as early as 10 dpf (Figure 2), and in adults this process leads to deformed vertebrae and ectopic mineralization foci deposited in between the vertebrae leading to a characteristic phenotype (Figure 3), reminiscent to some scoliosis models (Grimes et al, 2016).…”

Section: Discussionsupporting

confidence: 62%

“…Development of the Abcc6 −/− mouse models (Gorgels et al, 2005;Klement et al, 2005) resulted in fundamental discoveries related to the pathomechanism of PXE. In addition a number of attempts have been made to find or create suitable zebrafish models (Li et al, 2010;Mackay et al, 2015;Van Gils et al, 2018;Sun et al, 2021). Thanks to recent methodological developments and a number of advantageous features, the popularity of zebrafish as a pre-clinical disease model has been increasing over the past two decades (Lieschke and Currie, 2007;Varga et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…The latter two studies are also notable as they have used the mutants to screen for potential rescuing effects of vitamin K and the pyrophosphate analog etidronate, respectively. Finally, CRISPR/Cas9 and TALEN induced abcc6a mutant alleles have been also characterized more recently (Van Gils et al, 2018;Sun et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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A New Zebrafish Model for Pseudoxanthoma Elasticum

Czimer

Porok

Csete

et al. 2021

Front. Cell Dev. Biol.

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Calcification of various tissues is a significant health issue associated with aging, cancer and autoimmune diseases. There are both environmental and genetic factors behind this phenomenon and understanding them is essential for the development of efficient therapeutic approaches. Pseudoxanthoma elasticum (PXE) is a rare genetic disease, a prototype for calcification disorders, resulting from the dysfunction of ABCC6, a transport protein found in the membranes of cells. It is identified by excess calcification in a variety of tissues (e.g., eyes, skin, arteries) and currently it has no cure, known treatments target the symptoms only. Preclinical studies of PXE have been successful in mice, proving the usefulness of animal models for the study of the disease. Here, we present a new zebrafish (Danio rerio) model for PXE. By resolving some ambiguous assemblies in the zebrafish genome, we show that there are two functional and one non-functional paralogs for ABCC6 in zebrafish (abcc6a, abcc6b.1, and abcc6b.2, respectively). We created single and double mutants for the functional paralogs and characterized their calcification defects with a combination of techniques. Zebrafish deficient in abcc6a show defects in their vertebral calcification and also display ectopic calcification foci in their soft tissues. Our results also suggest that the impairment of abcc6b.1 does not affect this biological process.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

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A New Zebrafish Model for Pseudoxanthoma Elasticum

Czimer

Porok

Csete

et al. 2021

Front. Cell Dev. Biol.

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“…With small hearts, differences in intracellular calcium cycling, and scarce fibrosis, the anticipated value of modeling structural arrhythmias and chronic cardiac fibrosis related to HF in zebrafish is limited. However, some do report significant chronic cardiac fibrosis in zebrafish ( Huang et al, 2014 ; Sun et al, 2020 ). In addition to scarcity of chronic cardiac fibrosis in zebrafish, the same applies to lack of cardiac fatty tissue, a hallmark of human arrhythmogenic CM ( Gerull and Brodehl, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Zebrafish Heart Failure Models

Narumanchi

Wang

Perttunen

et al. 2021

Front. Cell Dev. Biol.

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Heart failure causes significant morbidity and mortality worldwide. The understanding of heart failure pathomechanisms and options for treatment remain incomplete. Zebrafish has proven useful for modeling human heart diseases due to similarity of zebrafish and mammalian hearts, fast easily tractable development, and readily available genetic methods. Embryonic cardiac development is rapid and cardiac function is easy to observe and quantify. Reverse genetics, by using morpholinos and CRISPR-Cas9 to modulate gene function, make zebrafish a primary animal model for in vivo studies of candidate genes. Zebrafish are able to effectively regenerate their hearts following injury. However, less attention has been given to using zebrafish models to increase understanding of heart failure and cardiac remodeling, including cardiac hypertrophy and hyperplasia. Here we discuss using zebrafish to study heart failure and cardiac remodeling, and review zebrafish genetic, drug-induced and other heart failure models, discussing the advantages and weaknesses of using zebrafish to model human heart disease. Using zebrafish models will lead to insights on the pathomechanisms of heart failure, with the aim to ultimately provide novel therapies for the prevention and treatment of heart failure.

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“…Thus, the abcc6a zebrafish model develops an abnormal calcification phenotype but one that does not recapitulate the human PXE. A new zebrafish model was recently created using the transcription activator-like effector nuclease (TALEN) technique [ 115 ]. These animals displayed similar skeletal changes as well as calcification in the ocular Bruch’s membrane and a range of other previously unreported manifestations, such as cardiac fibrosis.…”

Section: Animal Modelsmentioning

confidence: 99%

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

Shimada

Pomozi

Zoll

et al. 2021

IJMS

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Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

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Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis

Cited by 20 publications

References 52 publications

A New Zebrafish Model for Pseudoxanthoma Elasticum

A New Zebrafish Model for Pseudoxanthoma Elasticum

Zebrafish Heart Failure Models

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

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