Sculpting the labyrinth: epithelial morphogenesis in the zebrafish inner ear

This proposal aims to generate a multi-scale understanding of the remodelling events (fusion and perforation) that change the topology of an epithelial sheet during organogenesis. Failure of these processes underlies common congenital anomalies, such as ocular coloboma, spina bifida and cleft palate. We will study the developing zebrafish inner ear, which undergoes three rapid epithelial fusion and perforation events, each involving just a few cells. This model system is amenable to genetic, transgenic and pharmacological manipulation, and offers superb opportunities for live imaging. Key goals are to: - Use live imaging to map patterns of mitosis and apoptosis across the developing ear - Identify genetic requirements for cytoskeletal, adhesion and cell shape changes during inversion of epithelial curvature - Image and manipulate cell behaviour during epithelial fusion and perforation, including live imaging of cytoskeletal changes - Test the role of selected signalling pathways (aGPCR, Wnt/Fzd1, Netrin) in the fusion/perforation event - Test the role of apoptosis in remodelling during and after epithelial fusion/perforation The findings will improve our understanding of vertebrate otic organogenesis, with more general relevance to identify conserved modules of cell behaviour during epithelial morphogenesis. The project establishes new collaborations with experts on epithelial morphogenesis and cell signalling in other developing organ systems.