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Biol Open. 2019 Sep 9;8(9). pii: bio039834. doi: 10.1242/bio.039834.

Fgf8a mutation affects craniofacial development and skeletal gene expression in zebrafish larvae.

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Department of Orthodontics and Craniofacial Biology, Radboudumc, Nijmegen, The Netherlands.
Department of Orthodontics and Craniofacial Biology, Radboud Institute of Molecular Life Sciences, Nijmegen, The Netherlands.
Department of Animal Ecology and Physiology, Radboud University, Nijmegen, The Netherlands.
Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands.
Department of Oral Health Sciences and Department of Human Genetics, KU Leuven, Leuven, Belgium.
Department of Orthodontics and Craniofacial Biology, Radboudumc, Nijmegen, The Netherlands


Craniofacial development is tightly regulated and therefore highly vulnerable to disturbance by genetic and environmental factors. Fibroblast growth factors (FGFs) direct migration, proliferation and survival of cranial neural crest cells (CNCCs) forming the human face. In this study, we analyzed bone and cartilage formation in the head of five dpf fgf8ati282 zebrafish larvae and assessed gene expression levels for 11 genes involved in these processes. In addition, in situ hybridization was performed on 8 and 24 hours post fertilization (hpf) larvae (fgf8a, dlx2a, runx2a, col2a1a). A significant size reduction of eight out of nine craniofacial cartilage structures was found in homozygous mutant (6-36%, P<0.01) and heterozygous (7-24%, P<0.01) larvae. Also, nine mineralized structures were not observed in all or part of the homozygous (0-71%, P<0.0001) and heterozygous (33-100%, P<0.0001) larvae. In homozygote mutants, runx2a and sp7 expression was upregulated compared to wild type, presumably to compensate for the reduced bone formation. Decreased col9a1b expression may compromise cartilage formation. Upregulated dlx2a in homozygotes indicates impaired CNCC function. Dlx2a expression was reduced in the first and second stream of CNCCs in homozygous mutants at 24 hpf, as shown by in situ hybridization. This indicates an impairment of CNCC migration and survival by fgf8 mutation.


Bone; Cartilage; Craniofacial development; FGF8; Gene expression; Morphology; Zebrafish

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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