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Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption [scRNA-Seq]

ABSTRACT: Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function mutations. We elucidate the pathogenesis of limb reduction in an Esco2fl/fl;Prrx1-CreTg/0 mouse model using bulk- and single cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with the p53 inhibitor pifithrin-α, identified using a drug repositioning approach, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and human limb reduction disorders, suggesting etiological commonalities of cell death and vascular defects.

ORGANISM(S): Mus musculus

PROVIDER: GSE230492 | GEO | 2024/05/01

REPOSITORIES: GEO

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Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption [RNA-Seq]

Project description:Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function mutations. We elucidate the pathogenesis of limb reduction in an Esco2fl/fl;Prrx1-CreTg/0 mouse model using bulk- and single cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with the p53 inhibitor pifithrin-α, identified using a drug repositioning approach, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and human limb reduction disorders, suggesting etiological commonalities of cell death and vascular defects.

2024-05-01 | GSE230347 | GEO

The minor spliceosome is required for limb growth but not patterning

Project description:Diseases caused by mutations in components of the minor spliceosome frequently result in primordial dwarfism, where the limbs are stunted in size but retain pattern. We therefore sought to determine the role of the minor splieceosome in limb development by ablating an essential component, Rnu11, which encodes the U11 snRNA, in the mouse limb bud through Prrx1-Cre. We found that loss of U11 results in severe reduction in limb size at birth. However, mutant limbs retain proximo-distal patterning. Thus, we performed total RNAseq at E10.5 and E11.5 for both WT and mutant forelimb and hindlimb to determine the underlying molecular consequence of U11 loss and its effect on gene expression in the developing limb.

2020-07-22 | GSE146424 | GEO

Expression data from zebrafish depleted of Esco2

2011-03-01 | GSE27569 | GEO

Expression data from zebrafish depleted of Esco2

Project description:Our study in zebrafish is the first to use an animal model to understand the biology of the developmental disorder Roberts Syndrome (RBS). RBS is caused by mutations in the ESCO2 gene. We have used morpholinos (MO) to knock down esco2 in zebrafish to better understand the pathology of this rare human syndrome. Our zebrafish model nicely phenocopies the developmental defects observed in RBS. RNA from esco2 morphants and control (injected with buffer only) zebrafish embryos collected at 24 hours post-fertilization (h.p.f.) and 48 h.p.f. was hybridized to Affymetrix microarrays (Gene Chip zebrafish genome arrays cat. no. 900488). Four pools of 50 embryos for each genotype and time point were used as the RNA source, and RNA from each pool was hybridized independently such that the experiment had four biological replicates. Note that the chip for the 2nd replicate of the control embryos at 48 h.p.f. was faulty and the data is therefore not included.

2011-03-01 | E-GEOD-27569 | biostudies-arrayexpress

Proteome analysis of claws, clawless toe tips and back skin of Xenopus tropicalis

Project description:The aim of the study was to determine the protein composition of cornified claws of the western clawed frog (Xenopus tropicalis) in comparison to clawless toe tips and back skin. Cornified claws develop on toes I, II, III of the hind limbs, which we refer to as hind limb inner (HI) toes. Toes IV, V of the hind limbs, here referred to as hind limb outer (HO) toes lack claws. Proteins were prepared from HI toe tips including claws, HO toe tips and back skin (BSK) of frogs each (F1, F2, F3) and subjected to proteomic analysis.

2024-02-20 | PXD041765 | Pride

Identification and validation of gene expression changes upon removal of Dicer in the murine limb mesenchyme

Project description:Wild type and Dicer null embryonic mouse limbs were analaysed using Affymetrix arrays to identify gene expression changes. Genes that were up-regulated in Dicer-null limbs were canidates for being miRNA targets. Potential miRNA target genes were validated using qRTPCR. Mice carrying a heterozygous Dicer floxed allele and the prxcre driver allele were crossed to homozygous Dicer Floxed mice. Embryos were harvested from pregent moms and genotyped to determine heterozygous, Wild type and mutant limb buds. These limb buds were used to prepare RNA for array analysis.

2011-01-31 | E-GEOD-13807 | biostudies-arrayexpress

Differenetial Gene Expression in Limbs of Wild Type and Lmx1b KO mice during limb dorsalization (e11.5, e12.5 & e13.5)

Project description:Lmx1b regulates dorsalization of limb fates, but the mechanism of this regulation has not been characterized. To identify candidate genes regulated by Lmx1b we compared the limbs from Lmx1b KO mice to wild type mice during limb dorsalization (e11.5-13.5). Differentially expressed genes that we common to all three stages examined were considered to be likely candidates for Lmx1b regulation and further evaluated. At 11.5 and 12.5 dpc, embryos were harvested and the limb buds with the limb girdles were isolated. Embryos at 13.5dpc were also harvested and their distal limb buds (zeugopods and autopods) were isolated. Embryos were genotyped to confirm Lmx1b homozygosity (-/- or +/+). RNA from embryonic forelimbs and hindlimbs of wild type (WT) and Lmx1b KO mice was harvested using the Rneasy Kit (Qiagen). RNA was pooled to decrease genetic variability, i.e., six limbs at 11.5 dpc, three limbs at 12.5 dpc and six limbs at 13.5 dpc. Duplicate samples were generated using different embryos for each stage and then hybridized to the Affymetrix GeneChip® Mouse Genome 430 2.0 Array (UCI, Irvine, CA).

2012-05-21 | E-GEOD-34732 | biostudies-arrayexpress

Single-cell level transcriptomic anaylsis of the homeostatic and regenerating axolotl limb

Project description:Regeneration of complex multi-tissue structures, such as limbs, requires the coordinated effort of multiple cell types. In axolotl limb regeneration, the wound epidermis and blastema have been extensively studied via histology, grafting, and bulk-tissue RNA-sequencing. However, studying the contributions of these tissues is hindered due to limited information regarding the molecular identity of the cell types in regenerating limbs. By performing unbiased single-cell RNA-sequencing on over 25,000 cells from axolotl limbs, we identify a plethora of cellular diversity within epidermal, mesenchymal, and hematopoietic lineages in homeostatic and regenerating limbs. We identify regeneration-induced genes, develop putative trajectories for blastema cell differentiation, and propose the molecular identity and origin of fibroblast-derived blastema progenitor cells residing in homeostatic limbs. This work will enable application of molecular techniques to assess the contribution of these populations to limb regeneration. It will also facilitate work aimed at identifying transcripts and cells critical for limb regeneration.

2018-10-25 | GSE121737 | GEO

Extensive Functional Redundancy of Mammalian Enhancers [ChIP-seq]

Project description:Analysis of the epigenomic landscape in limbs of homozygous limb enhancer knockout mice

2018-01-01 | GSE93728 | GEO

Single-cell transcriptional landscape of human embryonic limb development - Mouse

Project description:To investigate into the evolutionary conversation of the single-cell transcriptome of human fetal limbs, especially the principles of forelimb and hindlimb specification and proximal-distal axis establishment, we collected the forelimbs and hindlimbs of mouse embryos matching human samples. We dissected the limbs to separate proximal, middle and distal parts and generated single-cell RNA-seq data of more than 70,000 cells. Combining this dataset with our human data, we are able to see highly conserved limb cell types and limb axis drivers.

2022-04-15 | E-MTAB-10514 | biostudies-arrayexpress

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