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Simultaneous induction of apoptosis, collagen type I expression and mineralization in the developing coronal suture
I M Mathijssen1, J P van Leeuwen, C Vermeij-Keers
1Institute of Plastic Surgery at the Erasmus University Rotterdam, The Netherlands. mathijssen@nvpc.nl
Abstract:
This study aimed to evaluate the disturbances in normal coronal suture development resulting in craniosynostosis, a congenital disorder in which the calvarial sutures close prematurely. Craniosynostosis syndromes can be caused by mutations in the genes encoding for the fibroblast growth factor receptors (FGFRs) 1, 2, and 3. These gain-of-function mutations cause the transcribed receptor to be constitutively activated. To mimic this genetic defect, fibroblast growth factor (FGF) 2 or 4 was administered near the developing coronal suture in normal mouse embryos through ex utero surgery. The effect on apoptosis and bone differentiation, as collagen type I expression and mineralization, within the FGF-exposed coronal suture was investigated through (immuno)histochemical staining. An increase in the number of apoptotic cells together with ectopic collagen type I expression within the suture and accelerated mineralization followed FGF application. Macroscopically, this presented as a synostotic coronal suture. These results suggest that both apoptosis and differentiation are two processes that are simultaneously implicated in synostosis of the coronal suture in case of a FGFR-related craniosynostosis.
Insights
Fibroblast growth factor (FGF) application in mouse embryos induced craniosynostosis by increasing cell death and bone formation. This suggests apoptosis and differentiation are key in FGFR-related craniosynostosis.
Area of Science:
- Developmental biology
- Genetics
- Craniofacial surgery
Background:
- Craniosynostosis is a congenital disorder characterized by premature closure of calvarial sutures.
- Mutations in fibroblast growth factor receptor (FGFR) genes are a common cause of craniosynostosis syndromes.
- Gain-of-function mutations in FGFRs lead to constitutive receptor activation.
Purpose of the Study:
- To investigate the molecular and cellular mechanisms underlying coronal suture fusion in FGFR-related craniosynostosis.
- To evaluate the impact of fibroblast growth factor (FGF) signaling on apoptosis and bone differentiation in developing coronal sutures.
Main Methods:
- Ex utero surgical administration of FGF2 or FGF4 to developing coronal sutures in normal mouse embryos.
- (Immuno)histochemical staining to assess apoptosis, collagen type I expression, and mineralization.
- Macroscopic evaluation of suture fusion.
Main Results:
- FGF application significantly increased apoptotic cell numbers within the coronal suture.
- Ectopic collagen type I expression and accelerated mineralization were observed in FGF-exposed sutures.
- Macroscopic examination revealed premature fusion (synostosis) of the coronal suture.
Conclusions:
- FGF signaling plays a critical role in regulating apoptosis and differentiation during coronal suture development.
- Both increased apoptosis and enhanced differentiation are implicated in the pathogenesis of FGFR-related coronal synostosis.
- This study provides insights into the cellular processes driving craniosynostosis, potentially informing therapeutic strategies.