Tissue fusion is an essential process during normal human development, and its dysregulation can result in common birth defects affecting a wide range of organs. Despite intense studies, precise mechanisms controlling fusion remain enigmatic. A critical step during eye development is fusion of the epithelial optic fissure margin. Coloboma, a structural failure of this optic fissure closure (OFC), is a leading cause of childhood blindness and ~ 70% of patients remain without a genetic diagnosis. Most of our current knowledge of coloboma causation comes from recurrent mutations disrupting signaling molecules, cell-proliferation regulators, or transcription factors (e.g. PAX2 and CHD7), and although some cell “behaviour” genes have recently been identified (e.g. ACTG1), how epithelial fusion occurs during OFC at the molecular, cellular and tissue levels, and how hierarchical factors control such mechanisms, is poorly understood.
Existing model organisms are not well suited to investigate fusion during OFC. Chick eyes represent a novel and highly appropriate system to bridge this gap for three key reasons: (i) their size, (ii) in ovo accessibility, and (iii) ex ovo culture and imaging techniques. We have developed an atlas of chick eye development and confirmed it as an excellent model for human OFC: chick OFC occurs over ~ 60-hours with a large fissure margin (~ 1.0mm), providing an ideal spatial-temporal analysis window. We have found that orthologous gene expression is highly conserved, and that cells at the fusion plate lose epithelial characteristics, dissolve basement membranes, and form intercalating cellular projections; common to other fusion contexts. Our complementary transcriptomic profiling analyses and filtering pipelines have identified multiple novel OFC fusion candidate genes. Genetic perturbation and live imaging is now a major focus of current work to test that these genes are essential for fusion, and to elucidate their function.