Speaker
Description
During development, cells self-organise into functional tissues through local interactions, yet the mechanisms coordinating form with function remain poorly understood. Müller glia (MG), the principal glia of the retina, establish non-overlapping territories that span all retinal layers, providing metabolic support and synaptic regulation. How MG coordinate territorial organisation during morphogenesis is unclear. Here I investigate the cellular dynamics and molecular mechanisms underlying MG territorial development in the zebrafish retina using in vivo imaging. MG morphogenesis was characterised throughout morphogenesis using high-resolution imaging (60-120 hours post-fertilisation), revealing progressive elaboration of processes in the neuropil, which coincided with neuronal synaptic maturation. MG branches become increasingly complex while territories transition from overlapping to spatially organised domains. To identify molecular regulators, I employed single-cell RNA sequencing datasets across these developmental timepoints, revealing dynamic expression of adhesion molecules, cytoskeletal regulators, and signalling pathways. Ligand-receptor interactome analysis identified candidate pathways mediating MG-neuron and MG-MG communication during development. HCR validation of 20 candidate genes confirmed MG expression across morphogenesis, with a subset showing dynamic upregulation coinciding with the onset of territorial establishment.
To evaluate what local cellular interactions are sufficient to generate spatial organisation and guide experimental focus, I developed an agent-based model of MG morphogenesis. Simulations implementing contact-mediated interactions demonstrated that homotypic repulsion alone can produce spatially organised territories, with branching rate emerging as a critical determinant of morphological complexity and territorial stability. Together, this work establishes a framework combining experimental observation with computational modelling to understand glial morphogenesis, revealing how complex tissue architecture can emerge from local perception-action loops in which individual cells sense their environment and adapt their form accordingly.
Lay Abstract
The retina, the light-sensitive tissue at the back of the eye, contains many cell types that must be precisely organised to allow us to see. Among these are Müller glia (MG), support cells that stretch across the full thickness of the retina and play essential roles in keeping neurons healthy and functioning. For the retina to work properly, MG cells must occupy its own distinct territory without overlapping with its neighbours. But how cells achieve this during development is not well understood. Using zebrafish as a model organism, I imaged living retinas at high resolution over several days of development, showing that MG progressively elaborate branches in a way that coincides with the maturation of nearby neurons, transitioning from overlapping to spatially organised domains. By analysing gene expression data from thousands of individual retinal cells, I identified 20 candidate genes expressed in MG at the right times to potentially regulate this process. Finally, I built a computer simulation showing that simple contact-based repulsion between neighbouring cells is sufficient to produce non-overlapping territories. Together, these findings reveal how organised tissue architecture can emerge from local cell-to-cell interactions, with implications for understanding both normal development and diseases where glial organisation is disrupted.
| Lay Title | Local Rules, Global Order: how retinal support cells self-organise during eye development |
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| Role | PhD Student |