Segmentation of the zebrafish axial skeleton relies on notochord sheath cells and not on the segmentation clock

Forero, Laura Lleras; Narayanan, Rachna; Huitema, Leonie F. A.; VanBergen, Maaike; Apschner, Alexander; Peterson-Maduro, Josi; Logister, Ive; Valentin, Guillaume; Morelli, Luis G.; Oates, Andrew C.; Schulte‐Merker, Stefan

doi:10.7554/elife.33843

Cited by 67 publications

(98 citation statements)

References 55 publications

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“…The structural demands on teleost notochords are particularly high given that larvae need to swim and feed as soon as embryogenesis concludes (Jiang & Smith 2007; Stemple et al 1996; Ellis et al 2014). Significantly, this happens before the ossification and formation of spines (Corallo et al 2018; Lleras Forero et al 2018; Wopat et al 2018; Fleming 2004; Gray et al 2014). This could explain the specific allocation of this desmoglein family member expression to the notochord.…”

Section: Discussionmentioning

confidence: 99%

“…In vertebrates the notochord is a transient structure and a precursor to spine formation, it is eventually almost entirely replaced by vertebrae (Fleming 2004; Stemple 2005; Corallo et al 2018; Lopez-Baez et al 2018; Gray et al 2014). Recently, it has been shown that correct spine patterning relies on segmentation cues present in the embryonic notochord (Wopat et al 2018; Lleras Forero et al 2018). This and other observations has led to the understanding that correct notochord morphogenesis is essential for normal spine formation (Fleming 2004; Lim et al 2017; Wopat et al 2018; Lleras Forero et al 2018; Gray et al 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, it has been shown that correct spine patterning relies on segmentation cues present in the embryonic notochord (Wopat et al 2018; Lleras Forero et al 2018). This and other observations has led to the understanding that correct notochord morphogenesis is essential for normal spine formation (Fleming 2004; Lim et al 2017; Wopat et al 2018; Lleras Forero et al 2018; Gray et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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The desmosomal cadherin Desmogon is necessary for the structural integrity of the Medaka notochord

Seleit

Gross

Woelk

et al. 2019

Preprint

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15The notochord is an embryonic tissue that acts as a precursor to the spine. It is composed of 16 outer sheath cells and inner vacuolated cells. Together they ensure the ability of the notochord 17 to act as a hydrostatic skeleton until ossification begins. To date, there is still a paucity in our 18 understanding of how the notochord cell types are specified and the molecular players 19 controlling both their formation and maintenance remain poorly understood. Here we report 20 that desmogon, a desmosomal cadherin, is essential for proper vacuolated cell shape and 21 therefore correct notochord morphology. We trace desmogon+ precursors and uncover an 22 early developmental heterogeneity that dictates the balance of vacuolated and sheath cell 23 formation. We demonstrate that the growth of vacuolated cells occurs asynchronously and 24 reveal the presence of distinct injury sensing mechanisms in the notochord. Additionally, using 25 a small-scale F0 CRISPR screen we implicate uncharacterized genes in notochordal integrity. 26 93 6 Results 94 95 desmogon is a fish-specific desmosomal cadherin expressed in the notochord 96

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The desmosomal cadherin Desmogon is necessary for the structural integrity of the Medaka notochord

Seleit

Gross

Woelk

et al. 2019

Preprint

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“…Although autonomous segmentation of the notochord was suggested as the developmental origin of segmental patterning of centra in teleosts, an influence by the paraxial mesoderm was demonstrated (Lleras-Forero et al 2018). Interestingly, loss of Meox1 function within the paraxial mesoderm, as seen within meox1 cho mutants (Nguyen et al 2014), leads to vertebrae defects.…”

Section: Discussionmentioning

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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“…Notochord formation in Xenopus has also been linked to the progressive activation of UPR via Xbp1 and Creb3l2 to drive its differentiation (21). Subsequently, the notochord ossifies to form the spine segments, while remnant notochord cells turn into the gel-like nucleus pulposus inside the intervertebral disks of the spinal column (22,23).…”

Section: Introductionmentioning

confidence: 99%

Active Receptor Tyrosine Kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish

D'Agati

Cabello

Frontzek

et al. 2018

Preprint

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The aberrant activation of developmental processes triggers diverse cancer types. Chordoma is a rare, aggressive tumor arising from transformed notochord remnants. Several potentially oncogenic factors, including several receptor tyrosine kinase (RTK) genes, have been found deregulated in chordoma, yet causation remains uncertain. In particular, sustained expression of the developmental notochord transcription factor Brachyury is hypothesized as key driver of chordoma; nonetheless, experimental evidence for an oncogenic role of Brachyury in chordoma and its prognostic impact remains missing. Here, we developed and applied a zebrafish chordoma model to identify the notochord-transforming potential of implicated genes in vivo. We find that Brachyury, including a form with augmented transcriptional activity, is insufficient to initiate notochord hyperplasia. In contrast, the chordoma-implicated RTKs EGFR and KDR/VEGFR2 are sufficient to transform notochord cells within two to five days of development. Transcriptome and structural analysis of transformed notochords revealed that the aberrant activation of RTK/Ras signaling attenuates processes required for notochord differentiation, including of the unfolded protein response. Our results provide first in vivo indication against a tumor-initiating potential of Brachyury in the notochord, and imply activated RTK signaling as possibly initiating event in chordoma. These results provide a mechanistic framework for the pursuit of chemotherapeutic compounds to combat this aggressive tumor type.

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Segmentation of the zebrafish axial skeleton relies on notochord sheath cells and not on the segmentation clock

Cited by 67 publications

References 55 publications

The desmosomal cadherin Desmogon is necessary for the structural integrity of the Medaka notochord

The desmosomal cadherin Desmogon is necessary for the structural integrity of the Medaka notochord

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

Active Receptor Tyrosine Kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish

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