title: 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.
authors: Department of Genetics, University College London Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, United Kingdom.
authors: Claire
authors: C
authors: Hippert
authors: Department of Genetics, University College London Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, United Kingdom.
authors: Anna B
authors: AB
authors: Graca
authors: Department of Genetics, University College London Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, United Kingdom.
authors: Amanda C
authors: AC
authors: Barber
authors: Department of Genetics, University College London Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, United Kingdom.
authors: Emma L
authors: EL
authors: West
authors: Department of Genetics, University College London Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, United Kingdom.
authors: Alexander J
authors: AJ
authors: Smith
authors: Department of Genetics, University College London Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, United Kingdom; NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, City Road, London, EC1V 2PD, United Kingdom.
authors: Robin R
authors: RR
authors: Ali
authors: Department of Genetics, University College London Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, United Kingdom.
authors: Rachael A
authors: RA
authors: Pearson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064531:Peripherins / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D012160:Retina / Q000473:pathology* / Q000503:physiopathology*; D012162:Retinal Degeneration / Q000503:physiopathology*; D014746:Vimentin / Q000378:metabolism
chemical_list: C453730:Crb1 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D064531:Peripherins; D011509:Proteoglycans; C578996:Prph2 protein, mouse; D014746:Vimentin; C528900:glial fibrillary astrocytic protein, mouse; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse