Developing new biophysical models of choroid fissure closure in zebrafish and foveal pit formation across species

PROJECT SUMMARY The proposed project is a physics and biology collaboration at the University of Northern Colorado (UNC) to model morphogenesis processes in the developing vertebrate eye. We will create new, quantitative, biophysical models of choroid fissure closure and of foveal pit formation, test these models against experimental data from

zebrafish and other organisms, and iterate to refine the models and maximize their predictive power. The project design is cutting-edge, yet accessible to undergraduate (UG) participation. UNC physics and biology majors will be recruited and engaged in all aspects of research, including experiment design and execution, computer

simulations, presentation of results at conferences, and preparation of manuscripts for submission to journals. The overall project goals are to: 1) address a basic research need for quantitative models of eye morphogenesis, incorporating key new data and unifying principles of central nervous system morphogenesis, 2) illuminate

relationships between molecular regulation and mechanical forces giving rise to shape changes in the eye, and 3) study mechanisms of developmental eye disorders, such as coloboma (failure of choroid fissure closure) and foveal hypoplasia (underdevelopment of the foveal pit). These goals align with NIH’s mission “to seek

fundamental knowledge about the nature and behavior of living systems” and with NEI’s strategic plan. They also target AREA priorities to provide UG research experiences and enhance the PUI’s research environment. We will achieve these goals by executing three independent Specific Aims. Aim 1 is to iteratively develop and

validate a novel bilayer vertex model of choroid fissure closure in zebrafish. In Aim 1a we will code the wildtype model into simulation software that can be run by undergraduates on a supercomputing cluster. In Aim 1b undergraduates will carry out experiments with zebrafish embryos, genetically and/or chemically manipulating

cadherins, actin, and “pioneer cells”. Each manipulation will correspond to a parameter in the bilayer vertex model, enabling validation and refinement of the model at each experimental step. Aim 2 is to extend a “tension- based morphogenesis” model of cerebellar foliation to the developing retina, with its similar cell types, but

different geometry and growth profile. We will determine if these model inputs lead to foveal shape outputs that resemble concaviclivate foveas seen in nature (preliminary results suggest they do). The model analysis will be incorporated as a project in the PUI’s existing required course, Computer Applications in Physics, as part of the

mathematical training for UG physics majors working on this Aim. Finally, Aim 3 builds on preliminary work, already involving four UGs, that investigates elastic creasing instability as a potential mechanism of foveal pit formation. Creases on compressed surfaces of elastomers bear a remarkable resemblance to convexiclivate

foveal pits such as those in Anolis lizards. We will specifically investigate creases formed in spherical shells that mimic the retinal geometry, and validate our experimental results with finite element simulations using the neo- Hookean hyperelastic model in COMSOL.