Dynamic decisions: Integrating dynamic gene expression with mechanical signals to understand retinogenesis and ocular disorders.

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The growth of an organ is a complex process that needs to be tightly controlled to ensure that structures in the body are correctly organised. Groups of cells must co-ordinate moving and changing shape with decisions to proliferate or specialise into mature cell types of the adult organ. My recent work has shown that during organ growth, genes are not simply on or off. Instead, the levels of some genes pulse dynamically over time, and this helps control whether cells decide to proliferate or specialise. It is not clear how changes in cell shape, tissue folding and mechanics are co-ordinated with the pulses in gene activity during cell decisions. This is particularly important in embryonic eye development and growth. Genetic changes in certain proteins which sense forces and tissue mechanics can lead to the eye disorders coloboma and microphthalmia. These eye disorders occur when the sequence of developmental steps in the growth of an eye in the womb are disrupted. Children born with microphthalmia have small under-developed eyes. Those with coloboma have a cleft or hole in one or more structures of the eye, such as the retina. These conditions affect vision, and there are currently no treatments. That coloboma, a structural tissue disorder, and microphthalmia, a disorder of cellular decisions, occur together suggests a two-way link between tissue mechanics and cell decisions. I will investigate how, within the developing eye, forces from tissue folding and movement affect cell fate gene activity over time. I will use state-of-the-art live imaging techniques that show gene activity in real time. I will introduce the genetic changes seen in coloboma and microphthalmia patients into 'mini-eyes' grown in a dish to investigate how these disorders occur. Understanding the links between mechanical signals and cell decisions will support development of innovative cell-based therapies. My work therefore has important implications for furthering understanding of developmental ocular disorders and innovative regenerative medicine approaches.