FGFR2 directs inhibition of WNT signaling to regulate anterior fontanelle closure during skull development
Lauren Bobzin1, Audrey Nickle1, Sebastian Ko1
1Center for Craniofacial Molecular Biology, Department of Biomedical Sciences, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
Insights
Fibroblast growth factor receptor 2 (FGFR2) signaling is crucial for skull development. Loss of FGFR2 disrupts anterior fontanelle (AF) closure by impairing FGF-WNT signaling, leading to abnormal skull formation.
Area of Science:
- Developmental Biology
- Genetics
- Craniofacial Development
Background:
- Calvarial sutures and fontanelles are vital for skull growth and birth.
- FGFR2 gene mutations cause craniosynostosis syndromes, leading to premature suture fusion and skull deformities.
Purpose of the Study:
- To investigate the role of Fibroblast Growth Factor Receptor 2 (FGFR2) in regulating anterior fontanelle (AF) closure.
- To elucidate the molecular mechanisms underlying AF closure and posterior frontal suture formation.
Main Methods:
- Utilized mouse genetics to study Fgfr2 function in skull development.
- Employed single-cell transcriptomics to analyze cell populations and gene expression within the AF.
- Investigated signaling pathways, including FGF and WNT, involved in suture formation.
Main Results:
- Identified SCX-expressing cells within the AF that differentiate into ligament, bone, and cartilage.
- Demonstrated that FGFR2 signaling in frontal bone osteogenic cells non-autonomously regulates AF cell differentiation.
- Found that FGFR2 signaling controls WNT pathway activity in AF cells via WIF1 expression.
Conclusions:
- FGFR2 signaling is essential for the proper differentiation of AF cells and the formation of the posterior frontal suture.
- An FGF-WNT signaling circuit, involving FGFR2 and WIF1, directs suture formation within the anterior fontanelle during postnatal development.
- Dysregulation of this circuit contributes to the craniofacial abnormalities observed in FGFR2-related disorders.
Abstract:
The calvarial bones of the infant skull are linked by transient fibrous joints known as sutures and fontanelles, which are essential for skull compression during birth and expansion during postnatal brain growth. Genetic conditions caused by pathogenic variants in FGFR2, such as Apert, Pfeiffer, and Crouzon syndromes, result in calvarial deformities due to premature suture fusion and a persistently open anterior fontanelle (AF). In this study, we investigated how Fgfr2 regulates AF closure by leveraging mouse genetics and single-cell transcriptomics. We find that AF cells, marked by the tendon/ligament factor SCX, are spatially organized into ecto- and endocranial domains that selectively differentiate into ligament, bone, and cartilage to form the posterior frontal suture. We show that AF cell differentiation is non-autonomously regulated by FGFR2 signaling in osteogenic front cells of the frontal bones, which regulate WNT signaling in neighboring AF cells by expressing the secreted WNT inhibitor Wif1. Upon loss of Fgfr2, Wif1 expression is downregulated, and AF cells fail to form the posterior frontal suture. This study identifies an FGF-WNT signaling circuit that that directs suture formation within the AF during postnatal development.
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