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Loss of Stim2 in zebrafish induces retinal gene expression cellular changes resembling glaucoma characteristics [RNA-seq]

ABSTRACT: Calcium is involved in vision processes in retina and is implicated in various pathologies including glaucoma. Rods are protected against prolonged lowering of intracellular calcium ion concentrations by Store Operated Calcium Entry (SOCE). We showed zebrafish lacking SOCE calcium sensor Stim2 had problem with vision as indicated by behavior tests, staining of retina and downregulation of genes related to light perception. In this work we aimed to understand the mechanism responsible for the vision problems in stim2 zebrafish knockout. scRNA-sequencing of neuronal origin cells from brains of 5 dpf larvae identified 27 clusters. Differently expressed genes were detected in ten clusters including amacrine and GABAergic retinal interneurons and GABAergic optic tectum cells. In five clusters the proportion of cells in stim2 KO fish versus control was significantly decreased including GABAergic diencephalon and optic tectum, and was increased in amacrine and GABAergic retinal interneurons. Transmission Electron Microscopy in stim2 KO fish revealed decrease in width of inner plexiform layer (IPL), ganglion cells and their dendrites numbers what is characteristic for glaucoma. Analysis of cell density in the inner nucleus layer, which includes amacrine cells among others, showed a significant decrease in the number of GABAergic neurons. The area of cristae in photoreceptor mitochondria was statistically lower in stim2 KO than in control retinas.

ORGANISM(S): Danio rerio

PROVIDER: GSE264309 | GEO | 2024/10/21

REPOSITORIES: GEO

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Project description:Systemic lupus erythematous (SLE) is a prototype of autoimmune disease. Lupus nephritis (LN) is one of the most serious complications of SLE. The development of autoreactive B cells and the production of autoantibodies have been critical for the initiation and progression of LN. Store-operated Ca2+ entry (SOCE) is the main Ca2+ influx pathway in lymphocytes and is essential for immune response . SOCE is mediated by Ca2+ release-activated Ca2+ (CRAC) channels which are comprised of stromal interaction molecule (STIM) and calcium release-activated calcium modulators (ORAI) . Mutations in genes encoding the CRAC channel abolish SOCE in cells of the immune system and cause severe combined immunodeficiency . Calcium signaling via ORAI1 has been involved in the pathogenesis of autoimmune diseases by driving Th17 differentiation . STIM1 deficiency significantly reduced Th1/Th17 responses and resulted in complete protection from experimental autoimmune encephalomyelitis . Compared to T cells, the roles of CRAC channel in B cells is far less clear. Ca²⁺/calmodulin (CaM)-dependent protein kinase2 (CaMK2) is a serine/threonine-specific protein kinase that is regulated by the Ca²⁺/CaM complex. CaMK2 has been involved in many signaling pathways and is necessary for Ca²⁺ homeostasis, T cell development and activation. CaMK4, another member of the CaMK family, has been shown to compromises podocyte function and promote renal diseases in LN. In the current study, we found that CRAC channel mediated calcium signaling is enhanced in B cells from patients with LN. CRAC channel inhibition by YM-58483 and knocked down of CRAC channel by ORAI1 or STIM2 siRNA led to suppression of CaMK2 signaling and decreased B cell differentiation. Lupus mice treated with CRAC channel inhibitor showed reduced anti-double stranded DNA antibodies (anti-dsDNA), decreased immune deposition in the glomeruli and improved renal function. CRAC channel mediates the development and progression of LN by promoting the differentiation of B cells into plasma cells.

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Loss of Stim2 in zebrafish induces retinal gene expression cellular changes resembling glaucoma characteristics [RNA-seq]

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