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

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

PROVIDER: PRJNA942962 | ENA |

REPOSITORIES: ENA

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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 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

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 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 II

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 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.

2023-05-19 | GSE227053 | 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

Functional analysis of Vsx2 super-enhancer reveals an autoregulatory network governing Vsx2 expression during retinogenesis [RNA-seq_mouse]

Project description:The roles of retinal cis-regulatory landscape in controlling the expression of gene regulatory networks important for retinogenesis remain poorly understood. Vsx2 is a transcription factor essential for retinal proliferation and bipolar cell differentiation but the molecular mechanisms underlying its developmental roles are unclear. Here, we profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal gene regulatory networks associated with Vsx2 during development. We defined an autoregulatory loop in which VSX2 binds and transactivates its own enhancer in association with the transcription factor PAX6 . The Vsx2 regulatory landscape contains elements that are required for Vsx2 expression, retinal proliferation and proper cell type differentiation. We further show that retinae in which the Vsx2 enhancer landscape has been largely deleted suffer a bias toward photoreceptor production. Genomic data indicate that VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in mouse and human retinae, including a conserved region nearby the rod-specifying factor Prdm1. We provide evidence that VSX2 associates with OTX2 and can act to suppress OTX2-dependent enhancer transactivation of Prdm1 enhancer. Taken together, our analyses illuminate important mechanistic insights on how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.

2022-07-13 | GSE196104 | GEO

Functional analysis of Vsx2 super-enhancer reveals an autoregulatory network governing Vsx2 expression during retinogenesis [ChIP-seq_mouse]

2022-07-13 | GSE196103 | GEO