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

Gaillard, Anne-Laure; Mohamad, Teddy; Quan, Feng B.; Cian, Anne De; Mosimann, Christian; Tostivint, Hervé; Pézeron, Guillaume

doi:10.1016/j.ydbio.2023.01.010

Cited by 12 publications

(28 citation statements)

References 61 publications

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“…Given the early and long-lasting upregulation of urp1/2 in rpgrip1l -/- fish, we attempted to rescue axis curvature by decreasing global Urp1/2 production via genetic means by downregulating urp2 expression level. To that end, we generated double ( rpgrip1l +/- ; urp2 +/- ) heterozygous fish using the recently generated urp2 deletion allele (12) and crossed them to produce double mutants. Using a curvature quantification method on whole fish (Supplementary Figure 3I and methods), we observed that the removal of one or two urp2 functional allele(s) in rpgrip1l -/- fish did not lower their curvature index (Figure 4B), neither at two mpf (Supplementary Figure 3 F) nor at four mpf (Supplementary Figure 3 G-H).…”

Section: Resultsmentioning

confidence: 99%

“…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 (12–15). Their combined mutations or the mutation of their receptor gene uts2r3 lead to scoliosis at adult stages (12,13,16).…”

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: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Djebar,

Anselme,

Pezeron

et al. 2024

Preprint

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“…In zebrafish, CSF-cNs are also involved in spine deformities reminiscent of AIS, which rely on the maintenance of a controlled expression level of Urp1 and Urp2, two neuropeptides expressed from the embryonic life to adulthood in these sensory neurons 33 . Indeed, urp1;urp2 double mutants were recently reported to develop AIS-like phenotypes is zebrafish 51 , 52 . Moreover, a downregulation of Urp1/2 peptides expression level was reported in AIS mutant models with defective Reissner fiber acting upstream of CSF-cNs 18 , 19 .…”

Section: Discussionmentioning

confidence: 99%

Loss of CSF-contacting neuron sensory function is associated with a hyper-kyphosis of the spine reminiscent of Scheuermann’s disease

Marie-Hardy

Lotfi

Messa

et al. 2023

Sci Rep

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Scheuermann’s disease, also referred to as Scheuermann’s kyphosis, is the second most frequent spine deformity occurring in humans after adolescent idiopathic scoliosis (AIS), both with an unclear etiology. Recent genetic studies in zebrafish unraveled new mechanisms linked to AIS, highlighting the role of the Reissner fiber, an acellular polymer bathing in the cerebrospinal fluid (CSF) in close proximity with ciliated cells and mechanosensory neurons lining the central canal of the spinal cord (CSF-cNs). However, while the Reissner fiber and ciliary beating have been linked to AIS-like phenotypes in zebrafish, the relevance of the sensory functions of CSF-cNs for human spine disorders remains unknown. Here, we show that the thoracic hyper-kyphosis of the spine previously reported in adult pkd2l1 mutant zebrafish, in which the mechanosensory function of CSF-cNs is likely defective, is restricted to the sagittal plane and is not associated with vertebral malformations. By applying orthopedic criteria to analyze the amplitude of the curvature at the apex of the kyphosis, the curve pattern, the sagittal balance and sex bias, we demonstrate that pkd2l1 knock-outs develop a phenotype reminiscent of Scheuermann’s disease. Altogether our work consolidates the benefit of combining genetics and analysis of spine deformities in zebrafish to model idiopathic spine disorders in humans.

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“…In zebrafish, the circulation of CSF modulates the geometry of the body axis during embryogenesis (Zhang et al ., 2018) and of the spine curvature in juvenile/adult zebrafish (Grimes et al ., 2016). Genetic investigations in zebrafish revealed that straight body axis formation and spine organogenesis rely on the expression of urotensin neuropeptides in the spinal cord by ciliated sensory neurons surrounding the central canal, referred to as CSF-contacting neurons (CSF-cNs) (Quan et al ., 2015; Zhang et al ., 2018; Bearce et al ., 2022; Gaillard et al ., 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, in scospondin mutants in which the RF forms in the embryo but is not maintained in juvenile stages (Troutwine et al ., 2020, Rose et al ., 2020), the body axis becomes straight during embryogenesis but later on, the spine undergoes 3D torsion at the juvenile stage, a hallmark of idiopathic scoliosis. Peptides from the family of urotensin (Urp1, Urp2) and their receptor Uts2r3 play a major role in straightening the body axis throughout life (Bearce et al ., 2022; Gaillard et al ., 2022). Remarkably, urotensin signaling is relevant in human patients with adolescent idiopathic scoliosis (Dai et al ., 2021; Xie et al, in press ).…”

Section: Introductionmentioning

confidence: 99%

The Reissner fiber under tension in vivo shows dynamic interaction with ciliated cells contacting the cerebrospinal fluid

Bellegarda

Zavard

Moisan

et al. 2023

Preprint

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The Reissner fiber (RF) is an acellular thread positioned in the midline of the central canal that forms together with cerebrospinal fluid (CSF)-contacting neurons (CSF-cNs) an axial sensory system detecting curvature in the spinal cord. How these components interact is unknown. Using in vivo imaging in larval zebrafish, we show that RF is under tension and resonates dorsoventrally. Focal RF ablations trigger retraction and relaxation of the fiber cut ends, with larger retraction speeds for rostral ablations. We built a mechanical model to estimate RF mechanical parameters and reveal that tension builds up rostrally along the fiber. After RF ablation, CSF-cN spontaneous activity decreased and ciliary motility changed, suggesting physical interactions between RF and cilia projecting into the central canal. We observed that motile cilia were caudally-tilted and frequently interacted with RF. We propose that the numerous ependymal motile monocilia contribute to RF heterogenous tension via weak interactions. Our work demonstrates that under tension, the Reissner fiber dynamically interacts with motile cilia generating CSF flow and spinal sensory neurons.

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

Cited by 12 publications

References 61 publications

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Loss of CSF-contacting neuron sensory function is associated with a hyper-kyphosis of the spine reminiscent of Scheuermann’s disease

The Reissner fiber under tension in vivo shows dynamic interaction with ciliated cells contacting the cerebrospinal fluid

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