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A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice II

ABSTRACT: These datasets contain the transcriptomes from E12.5 orJ-homozygous (orJ mutant) retinal tissues after organotypic culture of retina and lens for 24 hours in the presence or absence of the Retinoid-X-Receptor (RXR) antagonist HX531. The Retinoid X receptor gamma (Rxrg) gene was identified as a highly upregulated gene from the retinal RNA-Seq profile of the E12.5 orJ mutant compared to the orJ-heterozygous (control) (add in GEO accession numbers for that data). The goal of this analysis was to determine if blocking RXR activity would restore gene expression to wild type levels by comparing the retinal gene expression profiles of biological replicates from 100 nM HX531-treated and vehicle-treated (0.1% DMSO) cultures.

ORGANISM(S): Mus musculus

PROVIDER: GSE227053 | GEO | 2023/05/19

REPOSITORIES: GEO

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A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice

Project description:This SuperSeries is composed of the SubSeries listed below. The Vsx2 homeobox gene is expressed in the newly formed retinal domain during early eye development and mutations in the Vsx2 gene cause congenital microphthalmia. The primary disruptions in the early retina are compromised retinal identity (lineage infidelity), reduced proliferation, and delayed neurogenesis. One goal of the study was to use gene expression profiling to predict genetic interactions between Vsx2 and candidate functional interactors that contribute to the early retinal phenotype of the Vsx2-null mouse strain ocular retardation J (orJ). The orJ allele is a spontaneous, recessive allele caused by the presence of a premature stop codon in the Vsx2 homeodomain. The datasets contained within are from three independent experimental designs. One was to compare the retinal gene expression profiles from E12.5 embryos that are one of three genotypes: the orJ-homozygous mutant, the combinatorial orJ; Mitfmi heterozygous mutant, and the orJ-heterozygous mouse (control). Another analysis was to compare the gene expression profiles of E12.5 orJ-homozygous mutant retinal tissues cultured for 24 hour in the presence or absence of the RXR antagonist HX531. The other analysis was to compare the gene expression profiles of E12.5 orJ-homozygous mutant retinal tissues cultured for 24 hour in the presence or absence of the gamma-Secretase antagonist Dibenzazipine (DBZ).

2023-05-19 | GSE227056 | GEO

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice I

Project description:These datasets contain the transcriptomes from E12.5 orJ-homozygous (orJ mutant) retinal tissues after organotypic culture of retina and lens for 24 hours in the presence or absence of the gamma-Secretase inhibitor Dibenzazipine (DBZ). A trait of the orJ mutant retina is the persistence of retinal progenitor cells (RPCs) during development despite greatly reduced proliferation and delayed neurogenesis. This led us to test whether gamma secretase activity was maintaining the RPC population in the orJ mutant retina, possibly through Notch signaling. The goal of this analysis was to determine if blocking gamma-Secretase activity would shift RPCs from a progenitor to a neurogenic state by comparing the retinal gene expression profiles of biological replicates from 300 nM DBZ-treated and vehicle-treated (0.1% DMSO) cultures.

2023-05-19 | GSE227052 | GEO

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice III

Project description:These datasets contain the transcriptomes from E12.5 mouse retinal tissues from embryos carrying three different combinations of the Vsx2 ocular retardation J (orJ) allele and the Mitf mi (mi) allele: orJ-heterozygous, which serves as the control, orJ-homozygous, and orJ-homozygous; mi-heterozygous. The orJ allele is a recessive loss of function and the mi allele is semi-dominant. Mitf is direct target of repression by Vsx2 in the retina and is an established causal factor in the orJ ocular phenotype of microphthalmia. The goal of this analysis was to determine if blocking Mitf function in the orJ mutant would restore retinal gene expression to wild type levels. All libraries were prepared and sequenced together, facilitating direct comparisons of the gene expression profiles across the 3 genotypes.

2023-05-19 | GSE227055 | GEO

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 ocular retardation J mice.

Project description:BackgroundA goal of developmental genetics is to identify functional interactions that underlie phenotypes caused by mutations. We sought to identify functional interactors of Vsx2, which when mutated, disrupts early retinal development. We utilized the Vsx2 loss-of-function mouse, ocular retardation J (orJ), to assess interactions based on principles of positive and negative epistasis as applied to bulk transcriptome data. This was first tested in vivo with Mitf, a target of Vsx2 repression, and then to cultures of orJ retina treated with inhibitors of Retinoid-X Receptors (RXR) to target Rxrg, an up-regulated gene in the orJ retina, and gamma-Secretase, an enzyme required for Notch signaling, a key mediator of retinal proliferation and neurogenesis.ResultsWhereas Mitf exhibited robust positive epistasis with Vsx2, it only partially accounts for the orJ phenotype, suggesting other functional interactors. RXR inhibition yielded minimal evidence for epistasis between Vsx2 and Rxrg. In contrast, gamma-Secretase inhibition caused hundreds of Vsx2-dependent genes associated with proliferation to deviate further from wild-type, providing evidence for convergent negative epistasis with Vsx2 in regulating tissue growth.ConclusionsCombining in vivo and ex vivo testing with transcriptome analysis revealed quantitative and qualitative characteristics of functional interaction between Vsx2, Mitf, RXR, and gamma-Secretase activities.

| S-EPMC10689574 | biostudies-literature

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice

Project description:A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice

| PRJNA942964 | ENA

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice II

Project description:A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice II

| PRJNA942962 | ENA

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice III

Project description:A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice III

| PRJNA942967 | ENA

A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice I

Project description:A framework to identify functional interactors that contribute to disrupted early retinal development in Vsx2 mutant mice I

| PRJNA942963 | ENA

Comparative evaluation of the biological characteristics of a novel retinoid X receptor agonist and bexarotene

Project description:Retinoid X receptor (RXR) is a crucial and distinctive member of the nuclear receptor superfamily, which is involved in regulating various physiological processes. RXR agonists have the potential to treat Alzheimer’s disease (AD). In this study, we identified a novel RXR agonist superior to existing drugs after extensively exploring the biological properties of 6-hydroxy-3’-propyl-[1,1’-biphenyl]-3-propanoic acid (6OHA), a compound synthesized in our laboratory based on the structure of magnaldehyde B. 6OHA exhibited higher selectivity for RXRα over retinoic acid receptor (RARα) and lower transcriptional activity for RXRg compared to the existing RXR agonist bexarotene (Bex). RNA-sequencing analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggest that 6OHA and Bex exhibit similar gene expression patterns but have distinct transcriptional effects; 6OHA was more closely associated with chemotaxis and response to stimuli compared to Bex. Pharmacokinetic studies revealed that 6OHA exhibited faster intestinal absorption, reached higher concentrations in the brain and liver shortly after oral dministration, and was cleared from the body more rapidly than Bex, subsequently inducing target gene transcription in the brain. Bex increased serum triglyceride and decreased serum thyrotropin and free thyroxine levels, whereas 6OHA did not induce these adverse effects, attributable to the distinct properties of 6OHA as an RXR agonist compared to Bex. Our results highlight 6OHA as a promising RXR agonist for treating AD without any adverse effects.

2024-11-09 | GSE280976 | GEO

Characterizing the transcriptome of WT organoids, RXRi organoids and APCko tumoroids

Project description:To compare the effects of RXR inhibition to those of APC depletion on the intestinal epithelium, WT organoids were treated with either HX531 (RXRi) or vehicle (WT) and APCko tumorids were treated with vehicle only. We then performed gene expression profiling analysis using data obtained from mRNA-seq of the indicated organoid lines.

2024-10-17 | GSE239757 | GEO

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