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Development. 2018 May 8;145(9). pii: dev159418. doi: 10.1242/dev.159418.

Direct activation of chordoblasts by retinoic acid is required for segmented centra mineralization during zebrafish spine development.

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Department of Biology, Institute of Zoology - Developmental Biology, University of Cologne, 50674 Cologne, Germany
Department of Biology, Institute of Zoology - Developmental Biology, University of Cologne, 50674 Cologne, Germany.
Molecular Cardiovascular Biology Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA.
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611-2605, USA.
Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland.
Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, 48149 Münster, Germany.
CiM Cluster of Excellence (EXC-1003), WWU Münster, 48149 Münster, Germany.
Hubrecht Institute - KNAW & UMC Utrecht, 3584CT Utrecht, Netherlands.
CECAD Cluster of Excellence, University of Cologne, 50931 Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.


Zebrafish mutants with increased retinoic acid (RA) signaling due to the loss of the RA-inactivating enzyme Cyp26b1 develop a hyper-mineralized spine with gradually fusing vertebral body precursors (centra). However, the underlying cellular mechanisms remain incompletely understood. Here, we show that cells of the notochord epithelium named chordoblasts are sensitive to RA signaling. Chordoblasts are uniformly distributed along the anteroposterior axis and initially generate the continuous collagenous notochord sheath. However, subsequently and iteratively, subsets of these cells undergo further RA-dependent differentiation steps, acquire a stellate-like shape, downregulate expression of the collagen gene col2a1a, switch on cyp26b1 expression and trigger metameric sheath mineralization. This mineralization fails to appear upon chordoblast-specific cell ablation or RA signal transduction blockade. Together, our data reveal that, despite their different developmental origins, the activities and regulation of chordoblasts are very similar to those of osteoblasts, including their RA-induced transition from osteoid-producing cells to osteoid-mineralizing ones. Furthermore, our data point to a requirement for locally controlled RA activity within the chordoblast layer in order to generate the segmented vertebral column.


Centra; Chordoblast; Notochord; Retinoic acid; Spine; Vertebral body; Zebrafish

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