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bioRxiv · 10.1101/2025.10.07.680916

Arhgef18 is a component of the outer limiting membrane required for retinal homeostasis

Alonso-Carriazo Fernandez, A.·Liu, T.·Thomas, H.·Fan, X.·Matter, K.·Balda, M. S.
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Abstract

Biallelic ARHGEF18 mutations cause human adult-onset retinal degeneration. We now find that Arhgef18 associates with the retinal outer limiting membrane (OLM), an adherens junction between Muller glia and photoreceptors. Arhgef18 knockout in Muller glial cells led to OLM disruption and vision loss by P60. While mice developed morphologically normal retinas, retinal rosettes started to form by P8, and retinas then progressively degenerated with OLM disintegration, retinal thinning, and vascular leakage. ARHGEF18/p114RhoGEF depletion in Muller cells in culture confirmed disruption of junctional recruitment of OLM proteins. Depletion also induced activation of NF-{kappa}B and {beta}-catenin signalling, activation of the multifunctional kinase Tank-binding kinase 1 (TBK1) and reduced mitochondrial activity. TBK1 inhibition or directly supporting mitochondrial activity with nicotinamide attenuated NF-{kappa}B and {beta}-catenin signalling and rescued mitochondrial activity. Thus, Arhgef18 is essential for OLM maintenance, and its disruption leads to activation of mechanisms that are targetable for possible therapeutic approaches.

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Alonso-Carriazo Fernandez, A., Liu, T., Thomas, H., Fan, X., Matter, K., Balda, M. S.. 2025-10-07. Arhgef18 is a component of the outer limiting membrane required for retinal homeostasis. https://doi.org/10.1101/2025.10.07.680916

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