Understanding Idiopathic Scoliosis: A New Zebrafish School of Thought

Boswell, Curtis W.; Ciruna, Brian

doi:10.1016/j.tig.2017.01.001

Cited by 85 publications

(81 citation statements)

References 96 publications

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confidence: 99%

Loss of the Reissner Fiber and increased URP neuropeptide signaling underlie scoliosis in a zebrafish ciliopathy mutant

Vesque

Anselme

Pézeron³

et al. 2019

Preprint

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Cilia-driven movements of the cerebrospinal fluid (CSF) are involved in zebrafish axis straightness, both in embryos and juveniles [1,2]. In embryos, axis straightness requires ciliadependent assembly of the Reissner fiber (RF), a SCO-spondin polymer running down the brain and spinal cord CSF-filled cavities [3]. Reduced expression levels of the urp1 and urp2 genes encoding neuropeptides of the Urotensin II family in CSF-contacting neurons (CSF-cNs) also underlie embryonic ventral curvature of several cilia motility mutants [4]. Moreover, mutants for scospondin and uts2r3 (a Urotensin II peptide family receptor gene) develop scoliosis at juvenile stages [3,4]. However, whether RF maintenance and URP signaling are perturbed in juvenile scoliotic ciliary mutants and how these perturbations are linked to scoliosis is unknown. Here we produced mutants in the zebrafish ortholog of the human RPGRIP1L ciliopathy gene encoding a transition zone protein [5][6][7]. rpgrip1l -/zebrafish had normal embryogenesis and developed 3D spine torsions in juveniles. Cilia lining the CNS cavities were normal in rpgrip1l -/embryos but sparse and malformed in juveniles and adults.Hindbrain ventricle dilations were present at scoliosis onset, suggesting defects in CSF flow.Immunostaining showed a secondary loss of RF correlating with juvenile scoliosis.Surprisingly, transcriptome analysis of rgprip1l mutants at scoliosis onset uncovered increased levels of urp1 and urp2 expression. Overexpressing urp2 in foxj1-expressing cells triggered scoliosis in rpgrip1l heterozygotes. Thus, our results demonstrate that increased URP signaling drives scoliosis onset in a ciliopathy mutant. We propose that imbalanced levels of URP neuropeptides in CSF-cNs may be an initial trigger of scoliosis.

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mentioning

confidence: 99%

Loss of the Reissner Fiber and increased URP neuropeptide signaling underlie scoliosis in a zebrafish ciliopathy mutant

Vesque

Anselme

Pézeron³

et al. 2019

Preprint

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“…Despite their lack of a load-bearing spinal column and being more phylogenically removed from humans than mice, fish such as zebrafish are frequently used to model human spinal disease (Gorman & Breden, 2007;Boswell & Ciruna, 2017). The hallmark of Klippel-Feil syndrome is the fusion of cervical vertebrae.…”

Section: Discussionmentioning

confidence: 99%

“…Zebrafish (Danio rerio) has become a popular model system due to their genetic tractability, ex utero development and amenability to microscopy (Lieschke & Currie, 2007). Furthermore, zebrafish are increasingly employed to model human spinal diseases with a high degree of fidelity (Boswell & Ciruna, 2017). The zebrafish mutant choker (cho) carries a loss-offunction mutation in its orthologue of MEOX1, meox1 (Nguyen et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Skeletal malformations of Meox1‐deficient zebrafish resemble human Klippel–Feil syndrome

2018

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Klippel–Feil syndrome is a congenital vertebral anomaly, which is characterised by the fusion of at least two cervical vertebrae and a clinically broad set of symptoms, including congenital scoliosis and elevated scapula (Sprengel's deformity). Klippel–Feil syndrome is associated with mutations in MEOX1. The zebrafish mutant choker (cho) carries a mutation in its orthologue, meox1. Although zebrafish is being increasingly employed as fidelitous models of human spinal disease, the vertebral column of Meox1‐deficient fish has not been assessed for defects. Here, we describe the skeletal defects of meox1cho mutant zebrafish utilising alizarin red to stain bones and chemical maceration of soft tissue to detect fusions in an unbiased manner. Obtained data reveal that meox1cho mutants feature aspects of a number of described symptoms of patients who suffer from Klippel–Feil syndrome and have mutations in MEOX1. These include vertebral fusion, congenital scoliosis and an asymmetry of the pectoral girdle, which resembles Sprengel's deformity. Thus, the meox1cho mutant zebrafish may serve as a useful tool to study the pathogenesis of the symptoms associated with Klippel–Feil syndrome.

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“…Most studies on the importance of cilia-mediated flow have been performed on zebrafish, and some studies support a conserved role for CSF flow in spine development in mammals. For instance, developmental scoliosis is observed in human conditions associated with perturbations of CSF flow, including neural tube closure, spinal canal cyst and Chiari malformation [114]. Nonetheless, stenosis of the human central canal has been observed in the healthy population after the age of 10 years, yet it remains a subject of debate and raises questions to the function of the central canal in adult human physiology [81,115,116].…”

Section: Functions Of Ciliary Beating In the Development And Maintenamentioning

confidence: 99%

The role of motile cilia in the development and physiology of the nervous system

Ringers

Olstad

Jurisch‐Yaksi

2019

Phil. Trans. R. Soc. B

100

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Motile cilia are miniature, whip-like organelles whose beating generates a directional fluid flow. The flow generated by ciliated epithelia is a subject of great interest, as defective ciliary motility results in severe human diseases called motile ciliopathies. Despite the abundance of motile cilia in diverse organs including the nervous system, their role in organ development and homeostasis remains poorly understood. Recently, much progress has been made regarding the identity of motile ciliated cells and the role of motile-ciliamediated flow in the development and physiology of the nervous system. In this review, we will discuss these recent advances from sensory organs, specifically the nose and the ear, to the spinal cord and brain ventricles.

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Understanding Idiopathic Scoliosis: A New Zebrafish School of Thought

Cited by 85 publications

References 96 publications

Loss of the Reissner Fiber and increased URP neuropeptide signaling underlie scoliosis in a zebrafish ciliopathy mutant

Loss of the Reissner Fiber and increased URP neuropeptide signaling underlie scoliosis in a zebrafish ciliopathy mutant

Skeletal malformations of Meox1‐deficient zebrafish resemble human Klippel–Feil syndrome

The role of motile cilia in the development and physiology of the nervous system

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