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

Troutwine, Benjamin R; Gontarz, Paul; Minowa, Ryoko; Monstad-Rios, Adrian T.; Konjikusic, Mia J.; Sepich, Diane S.; Kwon, Ronald Y.; Solnica‐Krezel, Lilianna; Gray, Ryan S.

doi:10.1101/847301

Cited by 9 publications

(11 citation statements)

References 39 publications

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“…In rpgrip1l ∆/∆ , the RF fails to be maintained at the onset of scoliosis. Given that SCO-spondin mutants develop spine deformities [31], the loss of the RF in rpgrip1l ∆/∆ juveniles is a likely cause of scoliosis appearance.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Recent evidence based on the labeling of SCO-spondin-GFP have revealed that the Reissner fiber in vivo is dynamic as well as straight as an arrow [47], which suggests that the fiber is under high tension in vivo. Given the dimensions of the central canal in living larvae (typically 10 µm by 9 µm) compared to the height of CSF-cN apical extensions (typically 3-5 µm) and the very thin diameter of the fiber (about 200 nm), it is conceivable that at rest, the thin RF could sit in the center of the central canal away from CSF-cN apical extension.…”

Section: How Can the Rf And Csf-cns Interact To Sense Spinal Curvature?mentioning

confidence: 99%

“…Furthermore, mutants for a receptor of the urotensin related peptides, which are solely produced by CSF-cNs in the spinal cord, exhibit a torsion of the spine, reminiscent of adolescent idiopathic scoliosis [9]. Finally, a recent report indicated that hypomorphic mutations in the scospondin gene induce 3D deformation of the spine [47]. Altogether, recent studies indicate that sensory neurons contacting the cerebrospinal fluid together with the Reissner fiber may contribute to the generation and maintenance of the shape of the spine.…”

Section: Relevance For Development Of Body Axis and Spinementioning

confidence: 99%

Sensory Neurons Contacting the Cerebrospinal Fluid Require the Reissner Fiber to Detect Spinal Curvature In Vivo

et al. 2020

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Recent evidence indicate active roles for the cerebrospinal fluid (CSF) on body axis development and morphogenesis of the spine implying CSF-contacting neurons (CSF-cNs) in the spinal cord. CSF-cNs project a ciliated apical extension into the central canal that is enriched in the channel PKD2L1 and enables the detection of spinal curvature in a directional manner. Dorsolateral CSF-cNs ipsilaterally respond to lateral bending while ventral CSF-cNs respond to longitudinal bending. Historically, the implication of the Reissner fiber (RF), a long extracellular thread in the CSF, to CSF-cN sensory functions has remained a subject of debate.Here, we reveal using electron microscopy in zebrafish larvae that the RF is in close vicinity with cilia and microvilli of ventral and dorsolateral CSF-cNs. We investigate in vivo the role of cilia and the Reissner fiber in the mechanosensory functions of CSF-cNs by combining calcium imaging with patch-clamp recordings. We show that disruption of cilia motility affects CSF-cN sensory responses to passive and active curvature of the spinal cord without affecting the Pkd2l1 channel activity. Since ciliary defects alter the formation of the Reissner fiber, we investigated whether the Reissner fiber contributes to CSF-cN mechanosensitivity in vivo. Using a hypomorphic mutation in the scospondin gene that forbids the aggregation of SCO-spondin into a fiber, we demonstrate in vivo that the Reissner fiber per se is critical for CSF-cN mechanosensory function. Our study uncovers that neurons contacting the cerebrospinal fluid functionally interact with the Reissner fiber to detect spinal curvature in the vertebrate spinal cord.

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“…We then took advantage of the asynchrony in scoliosis onset to correlate, at a given stage, cilia defects at different levels of the CNS cavities with the spine curvature status (straight or curved) of rpgrip1l -/juveniles. We analyzed cilia defects in three CNS regions implicated in scoliosis appearance: the spinal cord central canal (since scoliosis develops in the spine), the forebrain choroid plexus (fChP) whose cilia defects have been associated to scoliosis in katnb1 -/fish (18) and the subcommissural organ (SCO), which secretes SCO-spondin whose absence leads to scoliosis (5,11).…”

Section: Defects At Sco Level Correlate With Scoliosis Appearance At ...mentioning

confidence: 99%

“…Cilia-driven movements of the cerebrospinal fluid (CSF) are involved in zebrafish axis straightness, both in embryos and juveniles (4,9) and are tightly linked to the assembly and maintenance of the Reissner fiber (RF), a SCO-spondin polymer secreted by the subcommissural organ (SCO) and running down the brain and spinal cord CSF-filled cavities (10). RF loss at embryonic stage in null sspo mutants is lethal while its loss at juvenile stage in hypomorphic sspo mutants triggers scoliosis with full penetrance (5,10,11). Signaling downstream of the RF in embryos implicates Urp1 and Urp2, two neuropeptides of the Urotensin 2 family expressed in ventral CSF-contacting neurons (CSF-cNs), which trigger dorsal muscle contraction in embryos and larvae (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Djebar,

Anselme,

Pezeron

et al. 2024

Preprint

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Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on the mutated gene. We dissected the mechanisms of scoliosis onset in a zebrafish mutant for therpgrip1lgene encoding a ciliary transition zone protein.rpgrip1lmutant fish developed scoliosis with near-total penetrance but asynchronous onset in juveniles. Taking advantage of this asynchrony, we found that curvature onset was preceded by brain ventricle dilations and concomitant to the perturbation of Reissner fiber polymerization and to the loss of multicilia tufts around the subcommissural organ. Rescue experiments showed that Rpgrip1l was exclusively required infoxj1a-expressing cells to prevent axis curvature. Transcriptomic and proteomic studies identified neuroinflammation associated with increased Annexin levels as a potential mechanism of scoliosis development inrpgrip1ljuveniles. Investigating the cell types associated withannexin2over-expression, we uncovered astrogliosis, arising in glial cells surrounding the diencephalic and rhombencephalic ventricles just before scoliosis onset and increasing with time in severity. Anti-inflammatory drug treatment reduced scoliosis penetrance and severity and this correlated with both reduced astrogliosis and macrophage/microglia enrichment around the diencephalic ventricle. Mutation of thecep290gene encoding another transition zone protein also associated astrogliosis with scoliosis. Thus, we propose that the onset of a feed-forward loop between astrogliosis, induced by perturbed ventricular homeostasis, and immune cells recruitment as a novel pathogenic mechanism of zebrafish scoliosis in ciliary transition zone mutants.

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

Cited by 9 publications

References 39 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

Sensory Neurons Contacting the Cerebrospinal Fluid Require the Reissner Fiber to Detect Spinal Curvature In Vivo

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

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