Müller Glia Activation in Response to Inherited Retinal Degeneration Is Highly Varied and Disease-Specific

Abstract

Despite different aetiologies, most inherited retinal disorders culminate in photoreceptor loss, which induces concomitant changes in the neural retina, one of the most striking being reactive gliosis by Müller cells. It is typically assumed that photoreceptor loss leads to an upregulation of glial fibrilliary acidic protein (Gfap) and other intermediate filament proteins, together with other gliosis-related changes, including loss of integrity of the outer limiting membrane (OLM) and deposition of proteoglycans. However, this is based on a mix of both injury-induced and genetic causes of photoreceptor loss. There are very few longitudinal studies of gliosis in the retina and none comparing these changes across models over time. Here, we present a comprehensive spatiotemporal assessment of features of gliosis in the degenerating murine retina that involves Müller glia. Specifically, we assessed Gfap, vimentin and chondroitin sulphate proteoglycan (CSPG) levels and outer limiting membrane (OLM) integrity over time in four murine models of inherited photoreceptor degeneration that encompass a range of disease severities (Crb1rd8/rd8, Prph2+/Δ307, Rho-/-, Pde6brd1/rd1). These features underwent very different changes, depending upon the disease-causing mutation, and that these changes are not correlated with disease severity. Intermediate filament expression did indeed increase with disease progression in Crb1rd8/rd8 and Prph2+/Δ307, but decreased in the Prph2+/Δ307 and Pde6brd1/rd1 models. CSPG deposition usually, but not always, followed the trends in intermediate filament expression. The OLM adherens junctions underwent significant remodelling in all models, but with differences in the composition of the resulting junctions; in Rho-/- mice, the adherens junctions maintained the typical rod-Müller glia interactions, while in the Pde6brd1/rd1 model they formed predominantly between Müller cells in late stage of degeneration. Together, these results show that gliosis and its associated processes are variable and disease-dependent.

Retina regeneration in zebrafish

“…Müller glia respond to retinal injury by hypertrophy and activation of cytoskeletal genes, like glial fibrillary acidic protein (Gfap) and vimentin 6 . Only rarely do Müller glia divide following retinal injury in mammals, and when they do they often result in fibrosis and glial scarring 4 .…”

Expression of peptidylarginine deiminase 4 in an alkali injury model of retinal gliosis

“…These cells provide trophic and structural support to neuronal cells of the retina [1],[2]. The glial cell reactivity that is observed in injury [6],[7],[8],[9] and disease models [10] is characterized by the upregulation of the type III intermediate filaments (IFs) vimentin and glial fibrillary acidic protein (GFAP) [6],[7]. GFAP and vimentin are cytoskeletal proteins that are normally expressed in uninjured astrocytes and Müller cells, respectively; their chronic upregulation is considered pathological [2],[11],[12].…”

Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina

“…It might be appropriate to view the GS at the far end of a gliosis continuum, with a checkpoint thanks to natural selection (Weil et al, 2008). After all, just within the mouse, Müller cell reactivity varies considerably depending on the inherited degeneration (Hippert et al, 2015). Moreover, different strains of mice subjected to experimental RD react differently to RD (Matsumoto et al, 2014).…”