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Regulation of retinal neurogenesis by somatostatin signaling

ABSTRACT: Purpose: Neuropeptide signaling has been reported to impact neurogenesis in the central nervous system. However, these studies have typically been conducted using pharmacological agents in ex vivo preparations, and in vivo evidence for their developmental function is generally lacking. The goal of this study is to identify the impact of somatostatin signaling on retinal neurogenesis and development both ex vivo and in vivo. Methods: Mouse retinal explants grown ex vivo from E14-P0 and treated with a range of doses of agonist for the somatostatin receptor Sstr2 were multiplexed according to the MULTI-seq protocol and used to generate a single scRNA-seq expression library. Retinas from P0 littermates representing an allelic series (+/+, +/-, -/-) of Sstr2 KO mice were mutliplexed according to the MULTI-seq protocol and used to generate a single scRNA-seq expression library. Retinas from P14 littermates representing an allelic series (+/+, +/-, -/-) of Sstr2 KO mice were mutliplexed according to the MULTI-seq protocol and used to generate a single scRNA-seq expression library. Sequencing was performed on an illumina sequencer. Bcl files were analyzed by Cellranger. Samples were deconvoluted with the deMULTIplex r package and clustering and gene expression analysis were performed with the Seurat and Monocle2 r packages. Results: Cell type proportions were found to be impacted by Sstr2 signaling ex vivo with increasing levels of Sstr2 agonist found to decrease photoreceptor proportion and increase primary progenitor proportion. Sstr2 KO was not found to have an impact on cell type proportion in vivo at either P0 or P14. Sstr2 pharmacologic manipulation and Sstr2 KO did produce complementary gene expression changes in neurogenic progenitors indicating that somatostatin signaling downregulates neurogenesis. Conclusions: Our study demonstrates a role for somatostatin in retinal development by downregulating neurogenesis in neurogenic progenitors. However, it also demonstrates that somatostatin signaling is dispensable for in vivo retinal development and likely redundant with other cell extrinsic signals released during the same period.

ORGANISM(S): Mus musculus

PROVIDER: GSE164741 | GEO | 2021/05/28

REPOSITORIES: GEO

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Project description:PURPOSE To identify retinal genes and their relevant expression pathways affected by intravitreal injections of dexamethasone and triamcinolone acetonide in mice at clinically relevant time points for patient care. METHODS Differential gene expression of over 34,000 well-characterized mouse genes, in the retinas of 6 weeks old C57BL/6J mice were analyzed after intravitreal steroid injections at 1 week and 1 month time points, using Affymetrix Mouse Genome 430 2.0 microarrays. The data were analyzed using GeneSpringGX11 and Ingenuity Pathway Analysis (IPA) microarray analysis software for biologically relevant changes. RESULTS A common gene pathway, with differentially activated genes for both steroids and time points was ‘Semaphorin Signaling in Neurons’, a member of ‘Axonal Guidance Signaling System’. At 1 week post-injections a common theme was activation of genes expressed in retinal glial cells, TNF alpha and TGF beta signaling pathways and upregulation of stress response proteins (Serpina3n, Cebpd), as well as neuropeptide signaling somatostatin receptor (Sstr2). Unique for Dex was the upregulation of acute phase proteins (Gfap, Cp, Edn2) as well as Plexna2, a semaphorin signaling receptor, while EphrinB receptor ephexin1 (Argef15) was downregulated. Folate signaling appears to be unique for TAA at 1 week (Folh1, Cubn), while aryl-hydrocarbon receptor (AhR) signaling might be important for both steroids at 1 month. CONCLUSIONS Understanding the molecular and genetic effects of intraocular steroid treatments is of clinical relevance. This in vivo study has elucidated several genes and pathways that are potentially altering the neuroprotective/neurodegenerative balance between glial and retinal ganglion cells during intravitreal steroid treatment. Total of 18 retinal samples were analysed. There were two time points, day7 and day30. Each time point had three groups: BSS control, DEX treatment and TAA treatment. Each group had three biological replicas.

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Regulation of retinal neurogenesis by somatostatin signaling

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