Durmishi, Xhuljana; (2025) Investigating the role of Hepacam in Müller Glial morphogenesis in the zebrafish retina. Doctoral thesis (Ph.D), UCL (University College London).

Text Durmishi PhD Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 November 2026. Download (55MB)

Abstract

Müller Glia (MG) are essential radial glial cells in the vertebrate retina. They provide structural and metabolic support to neurons, regulate synaptic activity and maintain retinal homeostasis. They do this thanks to their intricate morphology, particularly in the inner plexiform layer (IPL), where their processes interact with synapses to form tripartite connections. Despite their critical role, the molecular mechanisms regulating MG morphogenesis and the functional implications of their morphological specialisations remain poorly understood. This thesis uses the zebrafish retina as a model system to explore the role of a glia-enriched cell adhesion molecule, Hepacam, in MG development, spatial organisation and synaptic interactions. Through CRISPR-Cas9 mutagenesis and high-resolution imaging, I demonstrate that Hepacam is essential for regulating MG morphological complexity. Loss of hepacam led to reduced process outgrowth and elaboration in the IPL, disrupted territory establishment between neighbouring cells and, consequently, impaired interactions with ribbon synapses, a critical component for synaptic transmission in the retina. Rescue experiments further confirm that Hepacam is necessary and sufficient for establishing and maintaining MG morphological complexity and that the molecule operates through dose-sensitive and non-cell-autonomous mechanisms. The morphological deficits observed in MG directly correlate with functional impairments, as evidenced by diminished optokinetic responses (OKR) in zebrafish larvae. In adult zebrafish, hepacam deficiency results in selective neuronal loss, synaptic degeneration and microglial activation, suggesting long-term consequences of compromised glial support at the tripartite synapse. These findings position Hepacam as a key regulator of MG morphogenesis and highlight the importance of glial morphology in maintaining retinal circuitry and ensuring optimal visual function throughout life.

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