Climbing to the top: Substrate‐mediated migration of calvarial osteoblasts in development and disease

Abstract

Congenital defects affecting the formation of the skull roof, such as craniosynostosis (CS) or persistent fontanelles, can occur as a result of abnormal calvarial bone differentiation and growth. Our genetic lineage tracing experiments showed mouse calvarial bone progenitors originate from supraorbital arch mesenchyme cells and migrate to the apex. We lack a basic understanding of how calvarial bones grow towards the skull apex, which impacts the position, patterning, and fusion of sutures. Here, we identified a baso-apical graded expression of Fibronectin (FN1) protein preceding calvarial bone expansion. Conditional deletion of fibronectin in cranial mesenchyme causes diminished frontal bone apical expansion, patent fontanelles and partial CS of the coronal suture. Differential expression of FN1 protein is associated with human CS syndromes and present in the Apert syndrome mouse and zebrafish models. We hypothesize that calvarial bone primordia extend apically by Fn matrix-mediated cell migration and with dysregulation of this cell-substrate interaction can contribute to calvarial bone defects. To this end, we identified a specific role for Wiskott-Aldrich Syndrome Like (Wasl), a gene required for lamellipodia formation, in regulating apical expansion of calvarial bone progenitors without perturbing their differentiation or proliferation. Together, these data allow us to propose a new model where graded FN1 protein expression creates a directional substrate on which calvarial bone progenitors use Wasl-dependent lamellipodia to migrate. FN dysregulation can be a point of convergence for the diverse etiologies of CS and serve as a therapeutic target for calvarial bone defects and diseases.