Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA352740 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5002420_1.fastq.gz | Fastqsanger.gz | |||
| SRR5002420_2.fastq.gz | Fastqsanger.gz | |||
| SRR5002430_1.fastq.gz | Fastqsanger.gz | |||
| SRR5002430_2.fastq.gz | Fastqsanger.gz | |||
| SRR5002440_1.fastq.gz | Fastqsanger.gz |
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Project description:Signaling of the RET receptor is crucial for the migration, proliferation, differentiation and survival of enteric neural crest cells (ENCCs) that form the enteric nervous system (ENS). Disturbances in RET signaling are associated with ENS defects, as is seen in patients with Hirschsprung disease. However, the downstream effectors of RET signalling in ENCCs is largely unknown. This study aims to gain new insight into the pathways involved in or triggered by RET in ENCCs. We used microarrays to detect the gene expression of mouse embryonic ENCCs when we stimulated with GDNF compare to control without GDNF and also compare to the gene expression of mouse embryonic gut (all are isolated from mouse embryonic day 14.5). Our aim is to gain insight of RET-GDNF downstream effectors and also all signalling pathways that regulate by RET-GDNF in ENCCs during development.
2011-12-07 | GSE34208 | GEO
Project description:Despite extensive genetic heterogeneity, 72% of pathogenic alleles for Hirschsprung disease (HSCR) arise from coding and regulatory variants in genes of the RET and EDNRB gene regulatory network (GRN) in the enteric nervous system (ENS). Reduced signaling of these two receptors below a threshold in enteric neural crest-derived cells (ENCDCs) leads to a molecular tipping point at which otherwise lesser cellular defects result in aganglionosis. To elucidate the mechanisms leading to enteric neuronal loss from these genetic defects, we generated four strains of mice carrying reduced function alleles at Ret or Ednrb or both, along with their wildtype alleles. ENS tissue- and single-cell gene expression profiling of the developing and postnatal gastrointestinal tract in five mouse models, with various combinations of mutant alleles, revealed 3 major insights: (i) Ret and Ednrb deficiency, rather than complete loss, is sufficient to induce HSCR, (ii) Ret and Ednrb demonstrate strong trans interactions, and (iii) disruption of this interaction leads to cellular fate changes to compensate for neuronal loss. This study of targeted mouse models of a multifactorial disorder reveals how increasing dosage of genetic defects within a GRN leads to quantifiably increasing dysregulation from genotype to gene expression to cellular identity to function. Importantly, our studies establish that aganglionosis results only with severely reduced gene expression at both receptor genes and their consequent disruption of normal and compensatory cell fate trajectories.
2025-04-01 | GSE227574 | GEO
Project description:Despite extensive genetic heterogeneity, 72% of pathogenic alleles for Hirschsprung disease (HSCR) arise from coding and regulatory variants in genes of the RET and EDNRB gene regulatory network (GRN) in the enteric nervous system (ENS). Reduced signaling of these two receptors below a threshold in enteric neural crest-derived cells (ENCDCs) leads to a molecular tipping point at which otherwise lesser cellular defects result in aganglionosis. To elucidate the mechanisms leading to enteric neuronal loss from these genetic defects, we generated four strains of mice carrying reduced function alleles at Ret or Ednrb or both, along with their wildtype alleles. ENS tissue- and single-cell gene expression profiling of the developing and postnatal gastrointestinal tract in five mouse models, with various combinations of mutant alleles, revealed 3 major insights: (i) Ret and Ednrb deficiency, rather than complete loss, is sufficient to induce HSCR, (ii) Ret and Ednrb demonstrate strong trans interactions, and (iii) disruption of this interaction leads to cellular fate changes to compensate for neuronal loss. This study of targeted mouse models of a multifactorial disorder reveals how increasing dosage of genetic defects within a GRN leads to quantifiably increasing dysregulation from genotype to gene expression to cellular identity to function. Importantly, our studies establish that aganglionosis results only with severely reduced gene expression at both receptor genes and their consequent disruption of normal and compensatory cell fate trajectories.
2025-04-01 | GSE255963 | GEO
Project description:Signaling of the RET receptor is crucial for the migration, proliferation, differentiation and survival of enteric neural crest cells (ENCCs) that form the enteric nervous system (ENS). Disturbances in RET signaling are associated with ENS defects, as is seen in patients with Hirschsprung disease. However, the downstream effectors of RET signalling in ENCCs is largely unknown. This study aims to gain new insight into the pathways involved in or triggered by RET in ENCCs. We used microarrays to detect the gene expression of mouse embryonic ENCCs when we stimulated with GDNF compare to control without GDNF and also compare to the gene expression of mouse embryonic gut (all are isolated from mouse embryonic day 14.5). Our aim is to gain insight of RET-GDNF downstream effectors and also all signalling pathways that regulate by RET-GDNF in ENCCs during development. We performed gene expression profiling with RNA isolated from GDNF- (the RET ligand) stimulated and non-stimulated mouse ENCCs and also from mouse embryonic gut E14.5. We compare these three set of microarray data to each other and analyzed single-gene analysis methods. by this analysis we could detect genes that regulate by RET-GDNF signalling in ENCCs and by comparing data of ENCCs with and without GDNF to the expression data of mouse embryonic gut in the same stage of development, we could also detect gene that specifically express in ENCCs dependent and independently of RET-GDNF signalling. We analyzed the gene expression data of ENCCs with and without GDNF by gene set enrichment analysis (GSEA) to detect which pathways are down- and up-regulated by RET-GDNF signalling.
2011-12-07 | E-GEOD-34208 | biostudies-arrayexpress
Project description:Hirschsprung disease (HSCR) is a congenital enteric neuropathy caused by disrupted migration, proliferation, or differentiation of enteric neural crest-derived cells (ENCDCs), with pathogenic variants at the RET locus accounting for a major fraction of cases. While coding variants in RET are known to impair enteric nervous system (ENS) development, the contribution of non-coding regulatory elements remains incompletely understood. The greatest contribution of this risk is from a common variant (rs2435357) in an ENS-active, SOX10-bound RET enhancer (MCS+9.7) that reduces RET expression in vivo and triggers expression changes in other ENS genes in the human fetal gut. Here, we investigate the role of this enhancer during ENS development using a targeted mouse model by deleting mcs9.7. Single-cell RNA-seq profiling of wildtype and homozygous delmcs9.7/ delmcs9.7 embryos revealed an ~8% decrease in RET expression within ENS clusters, with no gross shifts in ENS cell type composition. Ret expression loss was limited to early differentiating neurons and inhibitory motor neurons, indicating cell-type-specific enhancer control. To identify the Ret functional threshold for normal ENS development, we also generated a compound heterozygous mouse (+/delmcs9.7/;+/CFP) that showed additive reductions in Ret expression in these same cell types and bidirectional feedback between Ret and its upstream transcription factor Sox10. We observed reduced expression of 19 cell cycle genes and significant loss of nNOS+ and VIP+ neurons, consistent with decreased inhibitory neuron network driven by loss of proliferation, a hallmark of HSCR. These findings establish a biphasic, cell-type-specific role for the mcs9.7 enhancer in modulating Ret dosage and reveal how subtle enhancer perturbations alter neural subtype specification without overt aganglionosis. Together, our work uncovers the functional consequences of a common RET enhancer variant offering new insights into gene regulatory mechanisms driving HSCR.
2025-08-18 | GSE304252 | GEO
Project description:Purpose: Determine how blocking retinoic acid receptor (RAR) signaling within enteric neural crest-derived cells (ENCDC) from E11.5 stomach or E13.5 colon alters mRNA abundance. These ENCDC become the enteric nervous system. Methods: Enteric nervous system precursors were isolated from mouse E11.5 stomach or E13.5 colon using fluorescence activated cell sorting to purify TdTomato or EYFP expressing cells respectively from fetal bowel. The RarαDN allele encodes a potent RAR dominant negative protein that is expressed after CRE-mediated DNA recombination. Tamoxifen-activated CRE-ERT2 was expressed from the Ret locus for E13.5 colon studies and mice were tamoxifen treated at E10.5 prior to cell sorting. The Wnt1Cre allele was employed for E11.5 stomach studies. RNA-SEQ was performed in quadruplicate using Illumina HiSeq 4000. Sequence reads that passed quality filters were aligned to remove repeat sequences and ribosomal RNA reads and then processed using RNA-Seq unified mapper (RUM) package. RUM files were visualized in the TessLA browser for subsequent analyses. Results: Transcriptional profiling shows RarαDN differentially impacts gene expression in E11.5 stomach and E13.5 colon enteric neural crest-derived cells (ENCDC) that become the enteric nervous system. Conclusions: Blocking of RAR signaling in ENCDC causes dramatic changes in gene expression during early development in a stage-specific manner.
2021-02-04 | GSE165344 | GEO
Project description:The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest cells (ENCCs) during enteric nervous system (ENS) development. Pathogenic RET loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences, and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single-cell RNA sequencing (scRNA-seq) on an enriched population of ENCCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCC cells with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes and that Ret LoF contributes to GI aganglionosis in multiple independent ways.
2021-12-30 | GSE192676 | GEO
Project description:The enteric nervous system (ENS) can control most essential gut functions owing to its organization into complete neural circuits consisting of a multitude of different neuronal subtypes. We used microarrays to identify transcription factor networks and signaling pathways involved in diversification and differentiation of enteric neurons during development of the enteric nervous system.
2017-12-05 | GSE100130 | GEO
Project description:Enteric nervous system is involved in the regulation of intestinal inflammation. We developped mouse primary cultures of enteric nervous system to study impact of LPS, as pro-inflammatory mediator, and of the pro-drug 6-mercaptopurine on enteric inflammatory pathways We used microarrays to detail the global programme of gene expression underlying enteric neuro-inflammation and identified classes of up-regulated genes during this process.
2021-04-02 | GSE171308 | GEO