Jaroszynska, Natalia; (2024) The role of Matrix Metalloproteinases 2 and 9 in Müller glial morphogenesis in the zebrafish retina. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glia are critical support cells of the nervous system. In order to impart their supportive functions, they must be positioned appropriately amongst neurons, blood vessels and other glia, however the precise mechanisms by which glia position themselves and integrate into the tissues are currently not well understood. Müller glia (MG) are the major support cells of the retina. Their intricate and specialised morphology enables them to contact neurons and provide functional and biophysical support, ultimately maintaining retinal homeostasis. MG are amongst the last-born cells of the retina, and thus undergo morphogenesis in a highly dense extracellular environment, composed of neighbouring neurons and the extracellular matrix (ECM). The work presented in this thesis uncovers a novel role for ECM modifying enzymes Matrix metalloproteinases (Mmps) 2 and 9 in the morphological elaboration of Müller glia in the developing zebrafish retina. Dynamically developing MG cells were found to contact ECM components in the different layers of the retina, and simultaneously produce ECM-remodelling enzymes, Mmp2 and 9. Pharmacological inhibition as well as genetic knock out of mmp2 and mmp9 in the zebrafish led to defective outgrowth and reduced complexity of MG processes in the synaptic layers, and consequently, a decreased ability to associate with neuronal synapses. I further show that pan-gelatinase mutants show visual dysfunction with age, likely as a result of reduced glial support at the tripartite synapse. These results demonstrate a novel role of gelatinases in glial morphogenesis, suggesting that MG-ECM interactions, and most likely the timely remodelling of the ECM by gelatinases, are important for the outgrowth of MG processes and their association with neuronal synapses. This work exemplifies the importance of Mmp2/9 activity in regulating MG morphology, with possible implications in retinal degenerative diseases, where morphological alterations in MG, the ECM and Mmp activity are often observed.

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