Resolving primary pathomechanisms driving idiopathic-like spinal curvature using a new katnb1 scoliosis model

Meyer-Miner, Anne; Gennip, Jenica L.M. Van; Henke, Katrin; Harris, Matthew P.; Ciruna, Brian

doi:10.1016/j.isci.2022.105028

Cited by 5 publications

(6 citation statements)

References 71 publications

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“…A response to CSF defects in rpgrip1l mutants is also suggested by the strong upregulation of Foxj1a and its target genes. foxj1a is also upregulated in the CNS of three other scoliotic models in addition to rpgrip1l , ptk7, sspo and katnb1 (18,19,48), suggesting that it constitutes a common response to similar ventricular and CSF defects. Interestingly, foxj1a expression is also upregulated upon zebrafish embryonic (62,63) or adult (58) spinal cord injury.…”

Section: Discussionmentioning

confidence: 92%

“…Since rpgrip1l is ubiquitously expressed in zebrafish (23), scoliosis could have different tissue origins, including a neurological origin as shown for the ptk7 and ktnb1 scoliotic fish (18,19). Indeed, no tissue-specific rescue has been performed yet in zebrafish ciliary gene mutants.…”

Section: Resultsmentioning

confidence: 99%

“…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: Resultsmentioning

confidence: 99%

“…Foxj1a-positive cell populations encompass both monociliated and multiciliated ependymal cells, radial glial progenitors, glial cells of the SCO and the ChP, as well as CSF-contacting sensory neurons in the spinal cord (19,27,57,58). Recent work suggested that impairment of ciliogenesis in the fChP of the katnb1 mutant could play a role in inducing axis curvature (18). In the case of the rpgrip1l mutant, we temporally uncorrelated fChP cilia defects from scoliosis onset.…”

Section: Discussionmentioning

confidence: 99%

“…However, whether RF maintenance and Urp1/2 signaling are perturbed in juvenile scoliotic mutants of genes encoding TZ proteins (“TZ mutants”) and how these perturbations are linked to scoliosis is unknown, especially because TZ mutants do not display any sign of embryonic or larval cilia motility defects (3). Moreover, two scoliotic models develop axial curvature while maintaining a RF showing that their curvature onset occurs independently of RF loss (17,18). Finally, neuro-inflammation has been described in a small subset of zebrafish IS models for which anti-inflammatory/anti-oxidant treatments (with NAC or NACET) partially rescue scoliosis penetrance and severity (5,19).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Djebar,

Anselme,

Pezeron

et al. 2024

Preprint

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Urp1 and Urp2 act redundantly to maintain spine shape in zebrafish larvae

Gaillard¹,

Mohamad²,

Quan³

et al. 2023

Developmental Biology

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Apoptotic mechanism of propofol-induced developmental toxicity in zebrafish embryos

Yuan

Jia

et al. 2023

PLoS ONE

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General anesthetics can cause neurological damage and long-term behavioral/cognitive impairment during fetal and early postnatal life. However, the adverse influence on embryo development induced by propofol is unclear. We used embryonic zebrafish to explore the effects of propofol on embryonic and larval growth and development, and the related apoptotic mechanism. Zebrafish embryos were immersed in propofol (1, 2, 3, 4, and 5 μg/ml) dissolved in E3 medium from 6 to 48 hours post fertilization (hpf). The survival rate, locomotion, heart rate, hatchability, deformity rate, and body length were analyzed at defined stages. Terminal deoxynucleotidyl transferase nick-end-labeling was used to detect zebrafish embryo apoptosis, and the expression levels of apoptosis-related genes were determined using quantitative real-time reverse transcription PCR and whole-mount in situ hybridization. Larvae at 48 hpf were anesthetized by immersion in E3 culture medium containing 2 μg/ml propofol, the reasonable anesthetic concentration for zebrafish embryos, which caused significant caudal fin dysplasia, light pigmentation, edema, hemorrhage, and spinal deformity, and decreased the hatchability, body length, and heart rate. The numbers of apoptotic cells in propofol-treated 12, 48 and 72 hpf embryos increased significantly, and the mRNA expression levels of intrinsic apoptosis pathway-related casp3a, casp3b, casp9, and baxb genes were upregulated, mainly in the head and tail. Propofol decreased apoptosis in the head and back of 24 hpf zebrafish, which was consistent with the mRNA expression analysis. Our findings demonstrated that zebrafish embryos and larvae exposed to propofol experienced developmental toxicity, which correlated with the intrinsic apoptosis pathway with casp3a, casp3b, casp9, and baxb as the key genes.

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Resolving primary pathomechanisms driving idiopathic-like spinal curvature using a new katnb1 scoliosis model

Cited by 5 publications

References 71 publications

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Urp1 and Urp2 act redundantly to maintain spine shape in zebrafish larvae

Apoptotic mechanism of propofol-induced developmental toxicity in zebrafish embryos

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