Age-Related Retinal Degeneration Resulting from the Deletion of Shp2 Tyrosine Phosphatase in Photoreceptor
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE269514 | GEO | 2024/08/08
REPOSITORIES: GEO
Similar Datasets
Project description:Hematopoietic stem and progenitor cells derived from a zebrafish model of Noonan syndrome, carrying a patient-associated Shp2-D61G mutation, display an expansion of monocyte/macrophage progenitors with an inflammatory gene expression signature.
2021-02-27 | GSE167787 | GEO
Project description:Mutations that decrease activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), causes Noonan syndrome with multiple lentigines or NSML (also called LEOPARD syndrome), while the gain-of-function mutations promotes several malignancies. Precisely how a spectrum of maladies ranging from developmental disorders to cancer are regulated by varying a solitary phosphatase activity is not clearly understood. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR and its target genes. The SANT domain of NCOR was identified as the epigenetic reader for pY54-H3 marks. NSML patients, SHP2 knock-in mice (which develops NSML), as well as ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation promoting tumor growth in prostate cancer patients.
2023-09-28 | GSE214870 | GEO
Project description:While dysfunction and/or death of light-detecting photoreceptor cells underlies most inherited retinal dystrophies, knowledge of the species-specific details of human rod and cone photoreceptor cell development remains limited. Here, we generate retinal organoids using induced pluripotent stem cells (iPSC) derived from a patient with genetic photoreceptor disease, an isogenic control, and an unrelated control. Organoids were sampled using single-cell RNA sequencing across the developmental window encompassing photoreceptor specification, emergence, and maturation; up to 260 days of in vitro differentiation. Using single-cell transcriptomics data, we reconstruct the rod photoreceptor developmental lineage and identify a branchpoint in development unique to the disease state that gives rise to a divergent rod photoreceptor cell population. We show that the rod-specific transcription factor NR2E3 is required for the proper expression of genes involved in phototransduction, including expression of the light-sensitive protein rhodopsin, which is absent in divergent rods. NR2E3-null rods additionally misexpress several cone-specific phototransduction genes at both the transcript and protein level. Using joint multimodal single-cell sequencing on late-stage retinal organoids, we further identify the specific putative regulatory sites where rod-specific factors act to steer rod and cone photoreceptor cell development. Importantly, these findings are strikingly different than that observed in rodent models of disease. Together, these data provide a roadmap of human photoreceptor development and leverage patient iPSCs to define the specific roles of rod transcription factors in photoreceptor cell emergence and maturation.
2024-04-01 | GSE236197 | GEO
Project description:Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from an improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal disease. Here we utilized human organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S-opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development.
2020-01-15 | GSE143669 | GEO
Project description:Purpose: The purpose of this study was to identify transcripts of rod photoreceptors of the zebrafish, an important animal model for vision science. Methods: Zebrafish rods, and non-rod retinal cells of the XOPS:eGFP transgenic line, were separated by cell dissociation and fluorescence-activated cell sorting (FACS), followed by RNA-seq. Validation studies used qPCR and in situ hybridization. Some transcripts were examined in sorted retinal cell populations of larval and juvenile retinas and regenerated adult retinas, and in a zebrafish model for rod degeneration. Results: At a false discovery rate of <0.01, 597 transcripts were upregulated in rods vs. non-rod retinal cells, and 1032 were downregulated. 13,324 total transcripts were detected in rods, including many not previously known to be expressed by rods. Transcripts enriched in rods from adult retinas were also enriched in rods from larval and juvenile retinas, and were also enriched in regenerated rods. Many transcripts enriched in rods were upregulated in retinas of wildtype retinas vs. those of a zebrafish model for rod degeneration. Conclusions: We report the generation of an RNA-seq dataset describing the rod transcriptome of the zebrafish, which is now available as a resource for further studies of rod photoreceptor biology and comparative transcriptomics.
2018-02-08 | GSE100062 | GEO
Project description:Mutation of rod photoreceptor-enriched transcription factors is a major cause of inherited blindness. We identified the orphan nuclear hormone receptor ERRβ as selectively expressed in rod photoreceptors. Overexpression of ERRβ induces expression of rod-specific genes in retinas of both wildtype and in Nrl-/- mice, which lack rod photoreceptors. Mutation of ERRβ results in dysfunction and degeneration of rods, while inverse agonists of ERRβ trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERRβ. ERRβ coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Furthermore, enhancing ERRβ activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERRβ is a critical regulator of rod photoreceptor function and survival, and suggest that ERRβ agonists may be useful in the treatment of certain retinal dystrophies. Affymetrix MOE430 microarrays were used to analyze the expression patterns of P21 mouse retinal tissues. The results were compared across the variable of Genotype, specifically ERRβ knockout versus wildtype.
2010-07-30 | E-GEOD-21944 | biostudies-arrayexpress
Project description:Both rod and cone photoreceptors are critical for mammalian vision yet they have important functional differences. In this study, we investigate patterns of DNA methylation and chromatin accessibility in mouse rods and cones. Unexpectedly, we find that a substantial fraction of hypo-methylated regions in the rod methylome are in inaccessible chromatin. These regions show marks of active regulatory regions earlier in neuronal development and could remain undermethylated in adult rods due to their highly compact chromatin. We further identify rod- and cone-enriched regions of accessible chromatin that correspond with cell type-specificity of nearby photoreceptor gene expression. We predict novel DNA signatures of rod and cone specificity and show that NR2E3 function is necessary for rods to gain their complete ensemble of epigenomic features. Taken together, our data capture the epigenomic landscapes of retinal rods and cones, including differences relevant to chromatin structure and photoreceptor biology.
2016-03-07 | GSE72550 | GEO
Project description:Inflammation potentiates JMML-like blood defects in Shp2 mutant Noonan syndrome
| PRJNA705198 | ENA
Project description:Purpose: Avian photoreceptors are a diverse class of neurons, comprised of four single cones, the two members of the double cone, and rods. Many distinctive features of photoreceptor subtypes, including spectral tuning, oil droplet size and pigmentation, synaptic targets and spatial patterning, have been well characterized, but the molecular mechanisms underlying these attributes have not been explored. Furthermore, the signaling events and transcriptional regulators driving the differentiation of these diverse photoreceptors are currently unknown. Methods: To identify genes specifically expressed in distinct chicken (Gallus gallus) photoreceptor subtypes, we developed fluorescent reporters that label photoreceptor subpopulations, isolated these subpopulations using fluorescence-activated cell sorting, subjected them to next-generation sequencing, and conducted differential expression analysis. Results: We identified hundreds of differentially expressed genes from photoreceptor subpopulations labeled with rhodopsin, red opsin, green opsin, and violet opsin reporters. These genes are involved in a variety of processes, including phototransduction, transcriptional regulation, cell adhesion, maintenance of intra- and extra-cellular structure, and metabolism. Of particular note are a variety of differentially expressed transcription factors, which may drive and maintain photoreceptor diversity, and cell adhesion molecules that may mediate spatial patterning of photoreceptors and act to establish retinal circuitry. Conclusions: These analyses provide a framework for future studies that will dissect the role of these various factors in the differentiation of avian photoreceptor subtypes. mRNA expression profiling of 5 pairs of photoreceptor subtypes isolated from chicken retinal explants, 3 replicates per sample
2014-09-01 | E-GEOD-59850 | biostudies-arrayexpress
Project description:Photoreceptor disorders are collectively known as retinal degeneration (RD), and include retinitis pigmentosa (RP), cone-rod dystrophy and age related macular degeneration (AMD). These disorders are largely genetic in origin; individual mutations in any one of >200 genes cause RD, making mutation specific therapies prohibitively expensive. A better treatment plan, particularly for late stage disease, may involve stem cell transplants into the photoreceptor or ganglion cell layers of the retina. Stem cells from young mouse retinas can be transplanted, and can form photoreceptors in adult retinas. These cells can be grown in tissue culture, but can no longer form photoreceptors. We have used microarrays to investigate differences in gene expression between cultured retinal progenitor cells (RPCs) that have lost photoreceptor potential, postnatal day 1 (pn1) retinas and the postnatal day 5 (pn5) retinas that contain transplantable photoreceptors. We have also compared FACS sorted Rho-eGFP expressing rod photoreceptors from pn5 retinas with Rho-eGFP negative cells from the same retinas. We have identified over 300 genes upregulated in rod photoreceptor development in multiple comparisons, 37 of which have been previously identified as causative of retinal disease when mutated. It is anticipated that this research should bring us closer to growing photoreceptors in culture and therefore better treatments for RD. This dataset is also a resource for those seeking to identify novel retinopathy genes in RD patients. We extracted whole retinas from postnatal day 1 (Pn1) and postnatal day 5 (Pn5) mice, and compared them with cultured RPCs derived from pn5 retinas, using Affymetrix mouse 430A_2 arrays. We also extracted cells from Rho-eGFP Pn5 retinas and FACS sorted them. GFP+ve cells represent immature rod photoreceptors, as they express the Rho-eGFP fusion protein, which is only expressed in rods. GFP-ve cells represent all other retinal neurons. These samples were amplified and compared using Affymetrix mouse 430A_2arrays, by Source Biosciences GMBH, Berlin, Germany. Results from immature rods were then compared with those from other retinal neurons, while results from whole Pn5 retinas were compared with Pn1 retinas (which don't yet express rod specific genes), and RPCs, which are glial precursors. RPCs were also compared with Pn1 retinas. Genes which showed changed expression profiles in at least 3/4 of comparisons were prioritised for further investigation.
2015-01-20 | E-GEOD-59201 | biostudies-arrayexpress