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Jerome E Roger, Jessica D Gumerson, Elena Braginskaja, Anand Swaroop; GSK3 kinases are critical for photoreceptor function and homeostasis. . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5527.
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© ARVO (1962-2015); The Authors (2016-present)
Posttranslational modifications allow rapid and reversible modifications, essential for adaptation to changing cellular microenvironments. Glycogen synthase kinase 3 (GSK3) alpha and beta are two highly conserved protein kinases involved in the regulation of many biological functions (i.e. cell division, axogenesis and apoptosis). GSK3-mediated phosphorylation mediates the stability of a wide range of proteins and their degradation by the proteasome system. GSK3 functions have been extensively studied in the brain especially in the context of neurodegenerative diseases. However, their role in the retina is poorly understood. In addition, because absence of both GSK3s in brain is lethal in mice, the retina offers a great opportunity to investigate their function in post-mitotic neurons. This study aims to identify in vivo the role of GSK3s during photoreceptor cell differentiation and homeostasis.
Gsk3α and Gsk3β-floxed mice (Gsk3αβf/f) were mated with mice carrying the Crx-promoter driving Cre recombinase (Crxp-Cre) to delete both kinases in photoreceptor precursors. The retinal photoreceptor phenotype was investigated by electroretinogram (ERG), qPCR and immunohistochemistry.
Gsk3αβf/f; Crxp-Cre mouse (CKO) retina At P21 shows no signs of retinal disease with normal lamination compared to Gsk3αβf/f controls. However, at 3-months of age, loss of both GSK3 kinases in photoreceptors leads to cell death with approximately 1 to 3 rows of nuclei remaining. Muller glial cells are also activated (GFAP-positive) with displaced nuclei. In contrast, deletion at the same age of either Gsk3α or Gsk3β has no effects. ERG recording on 1-month old CKO animals revealed a large decrease of the scotopic response (both a- and b-waves) with a delay of the b-wave response. Under photopic conditions, b-wave amplitude is also largely reduced in CKO compared to littermate controls.
Lack of Gsk3 kinases does not change photoreceptor fate but alters their function resulting in cell death. The exact kinetic of photoreceptor loss is under investigation as well as the correlation with the observed reduction in ERG response.
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