PUBLICATION

Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease

Authors
Bergen, D.J.M., Tong, Q., Shukla, A., Newham, E., Zethof, J., Lundberg, M., Ryan, R., Youlten, S.E., Frysz, M., Croucher, P.I., Flik, G., Richardson, R.J., Kemp, J.P., Hammond, C.L., Metz, J.R.
ID
ZDB-PUB-220126-15
Date
2022
Source
BMC Biology   20: 21 (Journal)
Registered Authors
Bergen, Dylan, Flik, Gert, Hammond, Chrissy, Metz, Juriaan R., Richardson, Rebecca
Keywords
Bone, Collagen, Extracellular matrix, Musculoskeletal disease, Ossification, Osteoblast, Scales, Transcriptomics, Zebrafish
MeSH Terms
  • Animals
  • Gene Expression Profiling
  • Humans
  • Zebrafish*/metabolism
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
PubMed
35057801 Full text @ BMC Biol.
Abstract
Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration.
We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10-3). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10-4), and estimated bone mineral density (eBMD, P< 2× 10-5). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10-24) or eBMD (SPP1, P=6× 10-20) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1P160X/P160X mutants predominantly showed mineralisation defects.
We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping