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Joint transcriptional disruption of Ret and Ednrb drives cell fate reversal in the Enteric Nervous System in Hirschsprung disease

ABSTRACT: Joint transcriptional disruption of Ret and Ednrb drives cell fate reversal in the Enteric Nervous System in Hirschsprung disease

PROVIDER: PRJNA1077307 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23886516_1.fastq.gz	Fastqsanger.gz
	SRR23886516_2.fastq.gz	Fastqsanger.gz
	SRR23886517_1.fastq.gz	Fastqsanger.gz
	SRR23886517_2.fastq.gz	Fastqsanger.gz
	SRR23886518_1.fastq.gz	Fastqsanger.gz

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Joint transcriptional disruption of Ret and Ednrb drives cell fate reversal in the Enteric Nervous System in Hirschsprung disease [bulkRNA-seq]

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

Joint transcriptional disruption of Ret and Ednrb drives cell fate reversal in the Enteric Nervous System in Hirschsprung disease [scRNA-Seq]

2025-04-01 | GSE255963 | GEO

Joint transcriptional disruption of Ret and Ednrb drives cell fate reversal in the Enteric Nervous System in Hirschsprung disease [bulkRNA-seq]

Project description:Joint transcriptional disruption of Ret and Ednrb drives cell fate reversal in the Enteric Nervous System in Hirschsprung disease [bulkRNA-seq]

| PRJNA945846 | ENA

Joint transcriptional disruption of Ret and Ednrb drives cell fate reversal in the Enteric Nervous System in Hirschsprung disease [scRNA-Seq]

Project description:Joint transcriptional disruption of Ret and Ednrb drives cell fate reversal in the Enteric Nervous System in Hirschsprung disease [scRNA-Seq]

| PRJNA1077311 | ENA

Joint transcriptional disruption of Ret and Ednrb drives cell fate reversal in the Enteric Nervous System in Hirschsprung disease

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-04-01 | GSE255964 | GEO

Single-cell RNA sequencing of small intestine neurons in Hirschsprung disease mice

Project description:This study was undertaken to identify gene expression changes in enteric neurons of Hirschsprung disease mice. Methods: We performed single-cell RNA sequencing of enteric nervous system cells isolated from the small intestine of Ednrb-knockout mice at age P14. Results: Through comparisons with published datasets of WT small intestine enteric neurons, we identify a missing neuronal population in the ganglionated small intestine of Hirschsprung disease mice. Conclusion: Single-cell RNA sequencing permits identification of cellular perturbations in Hirschsprung disease models.

2022-08-24 | GSE199683 | GEO

Transcriptome profile Carnegie Stage 22 gut of different RET haplotypes

Project description:Total mRNA seq was perfomed on human fetal gut tissue at CS22 on 3 samples having different RET haplotype which progressively reduce expression of RET. R haplotypes are resistant and S haplotypes are susceptible to Hirschsprung disease

2018-10-30 | GSE111341 | GEO

Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease

Project description:Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. The HSCR phenotype is highly variable with respect to gender, segment length of aganglionosis, familiality and the presence of additional anomalies. By molecular genetic analysis, a minimum of 11 neuro-developmental genes (RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZFHX1B, PHOX2B, KIAA1279, TCF4) are known to harbor rare high-penetrance mutations that confer a large risk to the bearer. In addition, two other genes (RET, NRG1) harbor common low-penetrance polymorphisms that contribute only partially to risk and act as genetic modifiers. To broaden this search, we examined whether a set of 67 proven and candidate HSCR genes harbored additional modifier alleles. In this pilot study, we utilized a custom-designed array CGH with ~33,000 test probes at an average resolution of ~185bp to detect gene-sized or smaller copy number variants (CNVs) within these 67 genes in 18 heterogeneous HSCR patients. Using stringent criteria, we identified CNVs at three loci (MAPK10, ZFHX1B, SOX2) that are novel, involve regulatory and coding sequences of these neuro-developmental genes and show association with HSCR in combination with other congenital anomalies. Two-condition experiment: Patient vs. Control. Sex-matched controls. Technical replicates: 4 were examined twice and 3 were studied in triplicate. Technical replicates: 408.3.1, 408.3.2 Technical replicates: 300.3.1, 300.3.2 Technical replicates: 354.3.1, 354.3.2 Technical replicates: 355.3.1, 355.3.2 Technical replicates: 63.3.1, 63.3.2, 63.3.3 Technical replicates: 122.7.1, 122.7.2, 122.7.3 Technical replicates: 413.3.1, 413.3.2, 413.3.3

2011-05-06 | E-GEOD-29051 | biostudies-arrayexpress

Testing the Ret and Sema3d genetic interaction in mouse enteric nervous system development

Project description:For most multigenic disorders, clinical manifestation (penetrance) and presentation (expressivity) are likely to be an outcome of genetic interaction between multiple susceptibility genes. Here, using gene knockouts in mice we evaluated genetic interaction between loss of Ret and loss of Sema3d, two Hirschsprung disease (HSCR) susceptibility genes. We intercrossed Ret and Sema3d double null heterozygotes to generate mice with the nine possible genotypes and assessed survival by counting various genotypes, myenteric plexus development by acetylcholinesterase (AchE) staining and embryonic day 12.5 (E12.5) gut transcriptome by RNA-sequencing. Survival rates of Ret wildtype, null heterozygote and null homozygote mice at E12.5, birth and weaning were not influenced by the genotypes at Sema3d locus and vice-versa. Loss of myenteric plexus was observed only in all Ret null homozygotes, irrespective of the genotypes at Sema3d locus, and Sema3d null heterozygote and homozygote mice had normal gut innervation. As compared to wildtype mice gut gene expression, loss of Ret in null homozygotes led to differential expression of ~300 genes, whereas loss of Sema3d in null homozygotes had no major consequence and there was no evidence supporting major interaction between the two genes influencing gut transcriptome. Overall, given the null alleles and phenotypic assays used, we did not find evidence for genetic interaction between Ret and Sema3d affecting survival, myenteric plexus formation or gut transcriptome.

2017-03-28 | GSE89627 | GEO

A gene regulatory network explains RET-EDNRB epistasis in Hirschsprung disease.

Project description:Disruptions in gene regulatory networks (GRNs), driven by multiple deleterious variants, potentially underlie complex traits and diseases. Hirschsprung disease (HSCR), a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We previously demonstrated that RET transcription in the ENS is controlled by an extensive GRN involving the transcription factors (TFs) RARB, GATA2 and SOX10 and other HSCR genes. We now demonstrate, using human and mouse cellular and animal models, that EDNRB is transcriptionally regulated in the ENS by GATA2, SOX10 and NKX2.5 TFs. Significantly, RET and EDNRB expression is regulated by their shared use of GATA2 and SOX10, and in turn, these TFs are controlled by EDNRB and RET in a dose-dependent manner. This study expands the ENS development GRN to include both RET and EDNRB, uncovers the mechanistic basis for RET-EDNRB epistasis and emphasizes how functionally different genes associated with a complex disorder can be united through a common GRN.

| S-EPMC7275776 | biostudies-literature

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