Abstract
ABSTRACTCraniofacial 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.
Highlights
In the human embryo, craniofacial development starts around week 4 with the formation of five facial prominences in the pharyngeal arches by the differentiation of cranial neural crest cells (CNCCs) into chondroblasts (Sperber et al, 2010; Hall and Hörstadius, 1989)
The largest reduction in size in both homo- and heterozygotes was found for the length of the ethmoid plate (32 and 24% lower than in wild type) and the length of the Meckel’s cartilage (36 and 24%, respectively)
In conclusion, bone and cartilage formation is impaired in fgf8ati282 homo- and heterozygous mutant larvae
Summary
Craniofacial development starts around week 4 with the formation of five facial prominences in the pharyngeal arches by the differentiation of cranial neural crest cells (CNCCs) into chondroblasts (Sperber et al, 2010; Hall and Hörstadius, 1989). These prominences give rise to the different parts of the face, including the mandible, maxilla, palate, lips and nose. Some parts of the adult craniofacial skeleton are formed by endochondral ossification that involves the replacement of a cartilage template by bone (Ornitz and Marie, 2015) FGFs are crucial in the development of the lip, palate and teeth (Stanier and Pauws, 2012; Nie et al, 2006)
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