The long-term goal of this research is to understand how non-muscle myosin II contractility is regulated in the context of cell migration and adhesion. Defects to non-muscle myosin II contractility can lead to a number of human diseases including cardiomyopathy, renal disease, deafness, and cranial-facial disorders. Recently, mutations to SPECC1L has been identified in patients with a spectrum of cranial-facial disorders. A population of cells, known as cranial neural crest cells appear to be the most severely affected by mutations to SPECC1L. Critically, it is this population of cells that eventually forms the facial and jaw structures during embryonic development. While it has been hypothesized that SPECC1L is associated with both the actin and microtubule cytoskeletons, data generated in my lab as well as evidence gathered from the literature, suggest a role for this protein in the regulation of non-muscle myosin II and cellular adhesion. Using a closely related Drosophila ortholog, Split Discs, we will interrogate the relationship between SPECC1L and its family members and non-muscle myosin II. Through a structure-function analysis we will determine how Split Discs is associating with non-muscle myosin II, and through high-resolution total internal reflection microscopy analyze how Split Discs regulates the formation of non-muscle myosin II filaments used during cellular contractility. We then will use several Drosophila cell lines to examine how Split Discs, through its regulation of non-muscle myosin II contractility, can regulate the formation, dynamics, and force generation cell produce through cell-matrix adhesions. Finally, we will test how Split Discs regulates cell- cell adhesion, a critical component to cranial neural crest cells as they migration by collective cell migration, meaning they maintain cell-cell adhesions as they migrate. Will use both and in vitro tissue-culture based model and an in vivo model of collective cell migration and migration to test our hypothesis. Our studies of the relationship between Split Discs and non-muscle myosin II will not only allow us to glean valuable information about how non-muscle myosin II functions during cell migration, and adhesion, but will also give us critical insight to the pathologies of craniofacial disorders.
Contractility generated by non-muscle myosin II is a fundamental cellular process and plays important roles in how cells change shape and migrate. Where, when, and to what degrees cells contract is critical to their homeostasis. Defects to the way cells contract can lead to variety of human developmental disorders and diseases, thus, a better understanding of how contractility is regulated will have broad implications in human health.
