Substrate-mediated collective cell migration in calvarial bone expansion and disease

点击翻译按钮获取中文摘要

Summary Congenital defects affecting the formation of the skull roof, such as craniosynostosis or persistent fontanelles, occur as a result of abnormal calvarial growth and differentiation. We lack a basic understanding of how calvarial bones grow, which in turn impacts the position, patterning, and fusion of sutures. The Harris and Atit laboratories recently uncovered an unexpected and intriguing role for cellular sensing of graded fibronectin matrix in preferentially regulating apical expansion of calvarial progenitors during mouse development. When cellular lamellipodia are inhibited, mouse calvarial osteoblasts fail to appropriately migrate resembling defects seen when we conditionally delete fibronectin. These findings are bolstered by data that fibronectin is misregulated in patients with craniosynostosis as well as animal models of this disease. We propose that graded fibronectin may act as a substrate for coordinated migration of calvarial osteoblast progenitors over the skull roof. Our central hypothesis is that calvarial growth and suture patency are dependent on fibronectin-directed calvarial progenitor cell expansion. Through three focused mechanistic and translational aims, we will directly test this model and hypothesis of fibronectin substrate-mediated migration underlying a diverse number of suture pathologies. First, we will assess outcomes of altered fibronectin expression in regulation of calvarial growth. Second, using newly established genetic lines in mouse and zebrafish, we will test the dependence on fibronectin adhesion and the role of lamellipodia-dependent cellular sensing of an extracellular gradient in apical expansion of calvaria. Third, we will capitalize on both patient and mouse models of craniosynostosis to assess commonality of fibronectin disruption in clinically relevant dysmorphologies and whether decreasing fibronectin expression rescues craniosynostosis in zebrafish and mouse models in vivo. Our unique genetic tools in both mouse and zebrafish will allow us to define the function of fibronectin guided lamellipodia-based collective cell movement in vivo during calvarial bone expansion and the impact of fibronectin deficiency on suture patency. Results from these studies will help detail the substrate-mediated cell migration of osteoblast progenitors and will lead to new strategies for targeted therapies of calvarial bone defects and craniofacial disorders.