GEO series

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

GSE255963 Mus musculus (mouse) Single-cell RNA-seq 10 samples Submitted 2025/04/01 Platform GPL24247

At a glance

Single-cell RNA-seq · mouse · 10 samples

What it is: Single-cell RNA-seqGene activity measured in thousands of individual cells, so cell types can be told apart.
Organism: Mus musculus (mouse)
Samples: 10 samples
Data you can get: A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper: Joint disruption of Ret and Ednrb transcription shifts cell fate trajectories in the enteric nervous system in Hirschsprung diseaseProceedings of the National Academy of Sciences of the United States of America · 2025

Summary (written by the submitters)

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.

Read the full summary ↓

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.

Published in

Joint disruption of Ret and Ednrb transcription shifts cell fate trajectories in the enteric nervous system in Hirschsprung disease

Fine RD, Chubaryov R, Fu M et al. · Proceedings of the National Academy of Sciences of the United States of America 2025 · PMID 41118220 · doi:10.1073/pnas.2507062122

This dataset

Open GSE255963 in finder → Find more mouse RNA-seq datasets →

Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓

2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE255963_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓

3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: Single-cell studies usually ship their counts as 10x files (matrix.mtx, barcodes.tsv, features.tsv), an .h5 file, or an .rds / .h5ad object that Seurat or Scanpy can open. Look for those among the supplementary files.

Also filed as BioProject PRJNA1077311 and SRA study SRP490037. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 41118220) ↗

Samples in this study

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+ 10 more — browse all 10 samples with per-sample file links →

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