MicroCT-based phenomics in the zebrafish skeleton reveals virtues of deep phenotyping in a distributed organ system

Hur, Matthew; Gistelinck, Charlotte; Huber, Philippe; Lee, Jane; Thompson, Marjorie H.; Monstad-Rios, Adrian T.; Watson, Claire J.; McMenamin, Sarah K.; Willaert, Andy; Parichy, David M.; Coucke, Paul; Kwon, Ronald Y.

doi:10.7554/elife.26014

Cited by 65 publications

(83 citation statements)

References 40 publications

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“…While these studies have demonstrated the power of X-ray imaging, in most cases the downstream analysis in terms of digital atlas, segmentation and morphometric analysis was not exploited with the exception of Wong et al ., who reported a morphometric CT based analysis of mouse mutant embryos 22 . Semi-automated segmentation of vertebrae has been used for a comparative analysis of mutant and wild type zebrafish 51 . Since our aim was to employ micro-CT data for comparative morphometric analysis of large sample sizes we implemented automated segmentation as a user friendly and fast image analysis.…”

Section: Discussionmentioning

confidence: 99%

Quantitative morphometric analysis of adult teleost fish by X-ray computed tomography

Weinhardt¹,

Shkarin²,

Wernet³

et al. 2018

Sci Rep

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Vertebrate models provide indispensable paradigms to study development and disease. Their analysis requires a quantitative morphometric study of the body, organs and tissues. This is often impeded by pigmentation and sample size. X-ray micro-computed tomography (micro-CT) allows high-resolution volumetric tissue analysis, largely independent of sample size and transparency to visual light. Importantly, micro-CT data are inherently quantitative. We report a complete pipeline of high-throughput 3D data acquisition and image analysis, including tissue preparation and contrast enhancement for micro-CT imaging down to cellular resolution, automated data processing and organ or tissue segmentation that is applicable to comparative 3D morphometrics of small vertebrates. Applied to medaka fish, we first create an annotated anatomical atlas of the entire body, including inner organs as a quantitative morphological description of an adult individual. This atlas serves as a reference model for comparative studies. Using isogenic medaka strains we show that comparative 3D morphometrics of individuals permits identification of quantitative strain-specific traits. Thus, our pipeline enables high resolution morphological analysis as a basis for genotype-phenotype association studies of complex genetic traits in vertebrates.

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Section: Discussionmentioning

confidence: 99%

Quantitative morphometric analysis of adult teleost fish by X-ray computed tomography

Weinhardt¹,

Shkarin²,

Wernet³

et al. 2018

Sci Rep

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show abstract

“…Moreover, recent advances in μCT-based methods enable detailed and rapid skeletal phenotyping of zebrafish mutants, which often have been resistant to such methodologies ( 24 ). Advances in processing and analysis have now allowed analysis of hundreds of morphological and densitometric traits in large sets of zebrafish skeletal mutants ( 25 ). In this work, we applied systematic collagen analysis with skeletal phenomics to characterize a large set of zebrafish with mutations in type I collagen genes, as seen in patients with different forms of classical OI and EDS, to assess to which extent key features of human type I collagenopathies are recapitulated.…”

mentioning

confidence: 99%

Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

Gistelinck

Kwon

Malfait

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceType I collagenopathies are a heterogenous group of connective tissue disorders, caused by genetic defects in type I collagen. Inherent to these disorders is a large clinical variability, of which the underlying molecular basis remains undefined. By systematically analyzing skeletal phenotypes in a large set of type I collagen zebrafish mutants, we show that zebrafish models are able to both genocopy and phenocopy different forms of human type I collagenopathies, arguing for a similar pathogenetic basis. This study illustrates the future potential of zebrafish as a tool to further dissect the molecular basis of phenotypic variability in human type I collagenopathies, to improve diagnostic strategies as well as promote the discovery of new targetable pathways for pharmacological intervention of these disorders.

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“…The scale was designed according to a pre-defined parameter (air, HU = −1,000, color index = 0) and scanning results (including water and phantoms) to generate the mapping reference between color index (0–255) and Hounsfield units (HUs; in our case, −1,000 to 3,184). The 3D rendering was done by using CTvox software (Bruker microCT, Kontich, Belgium) and the BMD was analyzed by using CTAn software (Bruker microCT, Kontich, Belgium) with the fourth (a Weberian vertebra) or all vertebrae as the region of interest ( Bird & Mabee, 2003 ; Hur et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Age, but not short-term intensive swimming, affects chondrocyte turnover in zebrafish vertebral cartilage

Jian

HuangFu

Lee

et al. 2018

PeerJ

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Both age and intensive exercise are generally considered critical risk factors for osteoarthritis. In this work, we intend to establish zebrafish models to assess the role of these two factors on cartilage homeostasis. We designed a swimming device for zebrafish intensive exercise. The body measurements, bone mineral density (BMD) and the histology of spinal cartilages of 4- and 12-month-old zebrafish, as well the 12-month-old zebrafish before and after a 2-week exercise were compared. Our results indicate that both age and exercise affect the body length and body weight, and the micro-computed tomography reveals that both age and exercise affect the spinal BMD. However, quantitative analysis of immunohistochemistry and histochemistry indicate that short-term intensive exercise does not affect the extracellular matrix (ECM) of spinal cartilage. On the other hand, the cartilage ECM significantly grew from 4 to 12 months of age with an increase in total chondrocytes. dUTP nick end labeling staining shows that the percentages of apoptotic cells significantly increase as the zebrafish grows, whereas the BrdU labeling shows that proliferative cells dramatically decrease from 4 to 12 months of age. A 30-day chase of BrdU labeling shows some retention of labeling in cells in 4-month-old spinal cartilage but not in cartilage from 12-month-old zebrafish. Taken together, our results suggest that zebrafish chondrocytes are actively turned over, and indicate that aging is a critical factor that alters cartilage homeostasis. Zebrafish vertebral cartilage may serve as a good model to study the maturation and homeostasis of articular cartilage.

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MicroCT-based phenomics in the zebrafish skeleton reveals virtues of deep phenotyping in a distributed organ system

Cited by 65 publications

References 40 publications

Quantitative morphometric analysis of adult teleost fish by X-ray computed tomography

Quantitative morphometric analysis of adult teleost fish by X-ray computed tomography

Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

Age, but not short-term intensive swimming, affects chondrocyte turnover in zebrafish vertebral cartilage

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