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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE227055 | 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

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

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

2022-07-13 | GSE196097 | GEO

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

Retinas from the Pex1-G844D mouse model of Zellweger spectrum disorder

Project description:Gene expression analysis of retinas from a mouse model of the mild form of Zellweger spectrum disorder (ZSD). Mice homozygous for the hypomorphic Pex1-G844D allele, the murine ortholog of the human PEX1-G843D mutation found in a subset of patients with autosomal recessive ZSD, develop phenotypes found in humans with a milder form of ZSD, including retinal degeneration and vision loss. Similar to humans, mice heterozygous for the hypomorphic Pex1-G844D allele do not display age-related retinal abnormalities. We conducted a comparative analysis of retinal gene expression profile from Pex1-G844D homozygous and heterozygous mice in order to investigate the pathomechanisms of vision loss in humans with mild forms of ZSD. Whole retinas were obtained from 4 mice homozygous and 4 mice heterozygous for the hypomorphic Pex1-G844D allele, the murine ortholog of the human PEX1-G843D mutation found in a subset of patients with autosomal recessive Zellweger spectrum disorder (ZSD). The former group of animals show abnormal age-related related retinal degeneration due to peroxisome assembly defect resulting from having two copies of the hypomorphic Pex1-G844D allele. The latter group of animals display no evidence of abnormal age-related retinal degeneration due to the presence of one wild type copy of the Pex1 gene. The overall goal was to identify differentially expressed genes between mice homozygous and heterozygous for the hypomorphic Pex1-G844D allele that are informative of the pathomechanisms of age-related retinal degeneration in the former group.

2013-12-15 | E-GEOD-52348 | biostudies-arrayexpress

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

Retinas from the Pex1-G844D mouse model of Zellweger spectrum disorder

2013-12-15 | GSE52348 | GEO

Identification of Evolutionarily Conserved VSX2 Enhancers in Retinal Development

Project description:Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of transcription factor Vsx2 in a developmental stage- and cell-type specific manner. In the present study, we examine the ability of these modules to drive retinal development between species. By inserting the human build of one Vsx2 SE module into a mouse with microphthalmia, eye size was rescued. To understand the implications of these SE modules in a model of human development, we generated human retinal organoids. Deleting one module results in small organoids, recapitulating the small-eyed phenotype of mice with microphthalmia, while deletion of the other module leads to a complete loss of ON cone bipolar neurons. This prototypical SE serves as a model for uncoupling developmental stage- and cell-type specific effects of neurogenic transcription factors with complex expression patterns. Moreover, by elucidating the gene regulatory mechanisms, we can begin to examine how dysregulation of these mechanisms contributes to phenotypic diversity and disease.

2024-06-04 | GSE268990 | GEO

RNA-seq of porcine inner ear stria vascularis

Project description:To clarify the effect of Mitf mutation on stria vascularis transcriptome and identify downstream-genes of Mitf pathway which responsible for hearing development, we employed high-throughput sequencing to analyze the transcriptome of MitfR/r and Mitfr/r stria vascularis. Compare the transcriptome difference between MITF mutated homozygous and heterozygous pigs.

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