Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

Gistelinck, Charlotte; Kwon, Ronald Y.; Malfait, Fransiska; Symoens, Sofie; Harris, Matthew P.; Henke, Katrin; Hawkins, M. Brent; Fisher, Shannon; Sips, Patrick; Guillemyn, Brecht; Bek, Jan Willem; Vermassen, Petra; Saffel, Hanna De; Witten, P. Eckhard; Weis, MaryAnn; Paepe, Anne De; Eyre, David R.; Willaert, Andy; Coucke, Paul

doi:10.1073/pnas.1722200115

Cited by 86 publications

(74 citation statements)

References 41 publications

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“…S6B). This phenotype is reminiscent of those described in other type I collagen mutants (54,55). By contrast, from crosses of heterozygous col5a1 +/− parents, homozygous col5a1 −/− mutants were under-represented at 11 dpf, and completely absent by 14 dpf (Fig.…”

Section: Resultssupporting

confidence: 77%

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

Rajan

Roger

Kocha

et al. 2020

Preprint

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24Blood vessels are vital to sustain life in all vertebrates. While it is known that mural cells (pericytes 25 and smooth muscle cells) regulate vascular integrity, the contribution of other cell types to vascular 26 stabilization has been largely unexplored. Using zebrafish, we identified sclerotome-derived 27 perivascular fibroblasts as a novel population of blood vessel associated cells. In contrast to pericytes, 28 perivascular fibroblasts emerge early during development, express the extracellular matrix (ECM) 29 genes col1a2 and col5a1, and display distinct morphology and distribution. Time-lapse imaging 30 reveals that perivascular fibroblasts serve as pericyte precursors. Genetic ablation of perivascular 31 fibroblasts results in dysmorphic blood vessels with variable diameters. Strikingly, col5a1 mutants 32show spontaneous hemorrhage, and the penetrance of the phenotype is strongly enhanced by the 33 additional loss of col1a2. Together, our work reveals dual roles of perivascular fibroblasts in vascular 34 stabilization where they establish the ECM around nascent vessels and function as pericyte 35 progenitors. 36 3 AUTHOR SUMMARY 37 38 Blood vessels are essential to sustain life in humans. Defects in blood vessels can lead to serious 39 diseases, such as hemorrhage, tissue ischemia, and stroke. However, how blood vessel stability is 40 maintained by surrounding support cells is still poorly understood. Using the zebrafish model, we 41 identify a new population of blood vessel associated cells termed perivascular fibroblasts, which 42 originate from the sclerotome, an embryonic structure that is previously known to generate the 43 skeleton of the animal. Perivascular fibroblasts are distinct from pericytes, a known population of 44 blood vessel support cells. They become associated with blood vessels much earlier than pericytes 45 and express several collagen genes, encoding main components of the extracellular matrix. Loss of 46 perivascular fibroblasts or mutations in collagen genes result in fragile blood vessels prone to 47 53 54The vascular system is crucial to the survival of vertebrates. Blood vessels must rapidly expand 55 and contract in response to systemic cues, but also maintain the stability to withstand the stress of 56 blood flow. To maintain their integrity, blood vessels are supported by a highly specialized 57 perivascular architecture comprised of blood vessel associated cells and the surrounding extracellular 58 matrix (ECM) (1,2). Compromised vascular integrity can result in devastating human diseases, such 59 as aneurysms, vascular malformations, and hemorrhagic strokes (3-6). However, how blood vessels 60 are stabilized by different perivascular components is still poorly understood. 61The prevailing model is that vascular stability is maintained at three different levels: endothelial 62 cells, mural cells and the surrounding ECM (2). First, blood vessels are lined by endothelial cells. 63Adherens and tight junctions between endothelial cells provide the primary barrier to passage o...

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Section: Resultssupporting

confidence: 77%

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

Rajan

Roger

Kocha

et al. 2020

Preprint

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“…Similarly, we show mutant models of col1a1 dmh14/+ (G1144Q) and col1a2 dmh54/+ (G736D) in zebrafish also cause a reduction in bone density (Fig. 3C) (20). These experiments confirm that changes to the loci under selection yield phenotypes consistent with those observed in E. maclovinus and species of the cryonotothenioid radiation.…”

Section: Main Textsupporting

confidence: 82%

“…3A, Table S5). The function of these genes are conserved among disparate lineages of vertebrates (20) and nonsynonymous mutations in these collagens can lead to severe osteogenesis imperfecta in humans (21). Notably, previous studies show that collagen1 expression is reduced in the developing skeleton of notothenioid embryos, providing further evidence that broad changes at collagen loci are associated with skeletal variation (22).…”

Section: Main Textmentioning

confidence: 90%

Historical contingency shapes adaptive radiation in Antarctic fishes

Daane¹,

Dornburg

Smits

et al. 2018

Preprint

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Adaptive radiation illustrates the links between ecological opportunity, natural selection, and the generation of biodiversity (1). Central to adaptive radiation is the association between a diversifying lineage and the evolution of key traits that facilitate the utilization of novel environments or resources (2, 3). However, is not clear whether adaptive evolution or historical contingency is more important for the origin of key phenotypic traits in adaptive radiation (4, 5). Here we use targeted sequencing of >250,000 loci across 46 species to examine hypotheses concerning the origin and diversification of key traits in the adaptive radiation of Antarctic notothenioid fishes. Contrary to expectations of adaptive evolution, we show that notothenioids experienced a punctuated burst of genomic diversification and evolved key skeletal modifications before the onset of polar conditions in the Southern Ocean. We show that diversifying selection in pathways associated with human skeletal dysplasias facilitates ecologically important variation in buoyancy among Antarctic notothenioid species, and demonstrate the sufficiency of altered trip11, col1a2 and col1a1 function in zebrafish (Danio rerio) to phenocopy skeletal reduction in Antarctic notothenioids. Rather than adaptation being driven by the cooling of the Antarctic (6), our results highlight the role of exaptation and historical contingency in shaping the adaptive radiation of notothenioids. Understanding the historical and environmental context for the origin of key traits in adaptive radiations provides context in forecasting the effects of climate change on the stability and evolvability of natural populations.

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“…All analyses were for vertebrae 1-16 [34]. Computation of standard scores, z-scores, and statistical testing using the global test were performed as previously described [34,35]. Wild type AB zebrafish were incrossed and one-cell embryos were injected with 1nL of injection mix containing 5µM EnGen Spy Cas9 NLS (NEB #M0646), 100 ng/µL sgRNA, and 25 ng/µL donor plasmid.…”

Section: Microct Scanning and Analysismentioning

confidence: 99%

The Reissner Fiber is Highly Dynamic in vivo and Controls Morphogenesis of the Spine

Troutwine

Gontarz²,

Minowa

et al. 2019

Preprint

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SummarySpine morphogenesis requires the integration of multiple musculoskeletal tissues with the nervous system. Cerebrospinal fluid (CSF) physiology is important for development and homeostasis of the central nervous system and its disruption has been linked to scoliosis in zebrafish [1, 2]. Suspended in the CSF is an enigmatic glycoprotein thread called the Reissner fiber, which is secreted from the subcomissural organ (SCO) in the brain and extends caudally through the central canal to where it terminates at the base of the spinal cord. In zebrafish, scospondin null mutants are unable to assemble the Reissner fiber and fail to extend a straight body axis during embryonic development [3]. Here, we describe zebrafish hypomorphic missense alleles, which assemble the Reissner fiber and straighten the body axis during early embryonic development, yet progressively lose the fiber, concomitant with the emergence of body curvature, alterations in neuronal gene expression, and scoliosis in adults. Using an endogenously tagged scospondin-GFP zebrafish knock-in line, we directly visualized Reissner fiber dynamics during the normal development and during the progression of scoliosis, and demonstrate that the Reissner fiber is critical for the morphogenesis of the spine. Our study establishes a framework for future investigations of mechanistic roles of the Reissner fiber including its dynamic properties, molecular interactions, and how these processes are involved in the regulation of spine morphogenesis and scoliosis.HighlightsHypomorphic mutations in zebrafish scospondin result in progressive scoliosisThe disassembly of the Reissner fiber in scospondin hypomorphic mutants results in the strong upregulation of neuronal receptors and synaptic transport componentsAn endogenous fluorescent knock-in allele of scospondin reveals dynamic properties of the Reissner fiber during zebrafish developmentLoss of the Reissner fiber during larval development is a common feature of zebrafish scoliosis models

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Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

Cited by 86 publications

References 41 publications

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

Historical contingency shapes adaptive radiation in Antarctic fishes

The Reissner Fiber is Highly Dynamic in vivo and Controls Morphogenesis of the Spine

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