Fibronectin 1 is required for suture patency and dysregulated across craniosynostosis models in the mouse.

The mammalian skull roof is comprised of calvarial bones, connected through fibrous sutures, that protect the brain and allow for growth. Premature suture closure, or craniosynostosis (CS), impedes expansion, impacting 1 in every 2500 newborns. Despite its genetic heterogeneity, with nearly 80 associated genes, CS manifests as a common phenotype, hinting at a convergent etiological mechanism. Recently, we described how graded expression of extracellular matrix protein Fibronectin (FN1) is required for apical expansion of calvaria and coronal suture patency. Dysregulated FN1 expression has been identified in two human CS syndromes, suggesting its potential as a convergent mechanism of CS. Here, we further investigate the cellular basis for the CS phenotype in the Fn1 mutant mouse. Graded expression of FN1 baso-apically in the cranial mesenchyme was variably dysregulated across mouse models of syndromic and non-syndromic CS and accompanied by diminished apical expansion of frontal bone primordia. In parallel, at later developmental stages we find ectopic osteogenic induction of Six2 + patent suture mesenchyme in the Fn1 mutant. These findings pinpoint FN1 as a crucial regulator of suture patency by modulating calvarial growth and driving cell identity, and differentiation, thus providing a potential target for matrix-mediated treatments.