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Mutation of Vsx genes in zebrafish highlights the robustness of the retinal specification network [RNA-Seq]

ABSTRACT: Genetic studies in human and mice have established a dual role for Vsx genes in retina development: an early function in progenitors’ specification, and a later requirement for bipolar-cells fate determination. Despite their conserved expression patterns, it is currently unclear to which extent Vsx functions are also conserved across vertebrates, as mutant models are available only in mammals. To gain insight into vsx function in teleosts, we have generated vsx1 and vsx2 CRISPR-Cas9 double knockouts (vsxKO) in zebrafish. Our electrophysiological and histological analyses indicate severe visual impairment and bipolar cells depletion in vsxKO larvae, with retinal precursors being rerouted towards photoreceptors or Müller glia fates. Surprisingly, neural retina is properly specified and maintained in mutant embryos, which do not display microphthalmia. We show that although important cis-regulatory remodelling occurs in vsxKO retinas during early specification, this has little impact at a transcriptomic level. Our observations point to genetic redundancy as an important mechanism sustaining the integrity of the retinal specification network, and to Vsx genes regulatory weight varying substantially among vertebrate species.

ORGANISM(S): Danio rerio

PROVIDER: GSE189737 | GEO | 2023/05/12

REPOSITORIES: GEO

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Mutation of Vsx genes in zebrafish highlights the robustness of the retinal specification network [ATAC-Seq]

Project description:Genetic studies in human and mice have established a dual role for Vsx genes in retina development: an early function in progenitors’ specification, and a later requirement for bipolar-cells fate determination. Despite their conserved expression patterns, it is currently unclear to which extent Vsx functions are also conserved across vertebrates, as mutant models are available only in mammals. To gain insight into vsx function in teleosts, we have generated vsx1 and vsx2 CRISPR-Cas9 double knockouts (vsxKO) in zebrafish. Our electrophysiological and histological analyses indicate severe visual impairment and bipolar cells depletion in vsxKO larvae, with retinal precursors being rerouted towards photoreceptors or Müller glia fates. Surprisingly, neural retina is properly specified and maintained in mutant embryos, which do not display microphthalmia. We show that although important cis-regulatory remodelling occurs in vsxKO retinas during early specification, this has little impact at a transcriptomic level. Our observations point to genetic redundancy as an important mechanism sustaining the integrity of the retinal specification network, and to Vsx genes regulatory weight varying substantially among vertebrate species.

2023-05-12 | GSE189738 | GEO

Identification of a modular super-enhancer in murine retinal development

Project description:Single cell RNA-sequencing shows cell type specific expression of genes in the retina. Single cell ATAC-sequencing of the wild type retina at multiple stages revealed that chromatin in the Vsx2 CRC SE, a stage- and cell type-specific core regulatory circuit super-enhancer (CRC-SE) upstream of the Vsx2 gene, was only open in bipolar cells in Region3 in adult retina. Chromatin in Region0 was open in retinal progenitor cells in E14.5 retina.

2021-11-16 | GSE169262 | GEO

Nucleome Dynamics during Retinal Development [scRNA-seq/scATAC-seq_Mm]

Project description:Single cell RNA-sequencing shows cell type specific expression of genes in the retina. Single cell ATAC-sequencing of the wild type retina revealed that chromatin in the Vsx2 CRC SE, a stage- and cell type-specific core regulatory circuit super-enhancer (CRC-SE) upstream of the Vsx2 gene, was only open in bipolar cells. Deletion of the Vsx2 CRC-SE in mice led to the loss of bipolar neurons in the retina, which was confirmed by scRNA-sequencing of Vsx2SEKO mice.

2020-12-31 | GSE164044 | 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

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

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

Nucleome Dynamics during Retinal Development[Hi-C_Mm]

Project description:The nuclei of rod photoreceptors in mice and other nocturnal species have an unusual inverted chromatin structure with centrally located heterochromatin that helps to focus light and improve photosensitivity. To gain a deeper understanding of this unique nuclear organization of rod photoreceptors, we have carried out Hi-C on retina at 3 stages of development and on purified rod photoreceptors. Predicted looping interactions from the Hi-C data were validated with fluorescent in situ hybridization (FISH). We discovered that a subset of genes important for retinal development, cancer and stress response in the retina are localized to the facultative heterochromatin domain in a developmental stage– and cell type–specific manner. We used machine learning to develop an algorithm based on our chromatin Hidden Markov Modeling (chromHMM) of retinal development to predict heterochromatin domains and study their dynamics during retinogenesis. FISH data for 264 genomic loci were used to train and validate the algorithm. These integrated data (https://pecan.stjude.cloud/retinalnucleome) were used to identify a developmental stage- and cell type-specific core regulatory circuit super-enhancer (CRC-SE) upstream of the Vsx2 gene that is required for bipolar neuron expression. Deletion of the Vsx2 CRC-SE in mice led to the loss of bipolar neurons in the retina.

2019-09-05 | GSE135465 | GEO

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