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Sequencing Reveals miRNAs Enriched in the Developing Mouse Enteric Nervous System [miRNA]

ABSTRACT: The enteric nervous system (ENS) is an essential network of neurons and glia in the bowel wall. Defects in ENS development can result in Hirschsprung disease (HSCR), a life-threatening condition characterized by severe constipation, abdominal distention, bilious vomiting, and failure to thrive. A growing body of literature connects HSCR to alterations in miRNA expression, but there are limited data on the normal miRNA landscape in the developing ENS. We sequenced small RNAs (smRNA-seq) and messenger RNAs (mRNA-seq) in ENS precursors of mid-gestation Ednrb-EGFP mice and compared them to aggregated RNA from all other cells in the developing bowel. Our smRNA-seq results identified 73 miRNAs that were significantly enriched and highly expressed in the developing ENS, with miR-9, miR-27b, miR-124, miR-137, and miR-488 as our top 5 miRNAs that are conserved in humans. However, contrary to prior reports, our follow-up analyses of miR-137 showed that loss of Mir137 in Nestin-cre, Wnt1-cre, Sox10-cre, or Baf53b-cre lineage cells had no effect on mouse survival or ENS development. Our data provide important context for future studies of miRNA in HSCR and other ENS diseases and highlight open questions about facility-specific factors in development.

ORGANISM(S): Mus musculus

PROVIDER: GSE250527 | GEO | 2023/12/26

REPOSITORIES: GEO

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Sequencing Reveals miRNAs Enriched in the Developing Mouse Enteric Nervous System [mRNA]

Project description:The enteric nervous system (ENS) is an essential network of neurons and glia in the bowel wall. Defects in ENS development can result in Hirschsprung disease (HSCR), a life-threatening condition characterized by severe constipation, abdominal distention, bilious vomiting, and failure to thrive. A growing body of literature connects HSCR to alterations in miRNA expression, but there are limited data on the normal miRNA landscape in the developing ENS. We sequenced small RNAs (smRNA-seq) and messenger RNAs (mRNA-seq) in ENS precursors of mid-gestation Ednrb-EGFP mice and compared them to aggregated RNA from all other cells in the developing bowel. Our smRNA-seq results identified 73 miRNAs that were significantly enriched and highly expressed in the developing ENS, with miR-9, miR-27b, miR-124, miR-137, and miR-488 as our top 5 miRNAs that are conserved in humans. However, contrary to prior reports, our follow-up analyses of miR-137 showed that loss of Mir137 in Nestin-cre, Wnt1-cre, Sox10-cre, or Baf53b-cre lineage cells had no effect on mouse survival or ENS development. Our data provide important context for future studies of miRNA in HSCR and other ENS diseases and highlight open questions about facility-specific factors in development.

2023-12-26 | GSE250526 | GEO

Human enteric nervous system progenitor transplantation restores functional responses in Hirschsprung Disease patient-derived tissue

Project description:Objective Hirschsprung disease (HSCR) is a severe congenital disorder affecting 1:5000 live births. HSCR results from failure of enteric nervous system (ENS) progenitors to fully colonise the gastrointestinal tract during embryonic development. This leads to aganglionosis in the distal bowel, resulting in disrupted motor activity and impaired peristalsis. Currently, the only viable treatment option is surgical resection of the aganglionic bowel. However, patients frequently suffer debilitating, lifelong symptoms, with multiple surgical procedures often necessary. Hence, alternative treatment options are crucial. An attractive strategy involves the transplantation of ENS progenitors generated from human pluripotent stem cells (hPSCs). Design ENS progenitors were generated from hPSCs using an accelerated protocol and characterised, in detail, through a combination of single cell RNA-sequencing, protein expression analysis and calcium imaging. We tested ENS progenitors’ capacity to integrate and restore functional responses in HSCR colon, after ex vivo transplantation to organotypically cultured patient-derived colonic tissue, using organ bath contractility. Results We found that our protocol consistently gives rise to high yields of cell populations exhibiting transcriptional and functional hallmarks of early ENS progenitors. Following transplantation, hPSC-derived ENS progenitors integrate, migrate and form neurons within explanted human HSCR colon samples. Importantly, the transplanted HSCR tissue displayed increased basal contractile activity and increased responses to electrical stimulation compared to control tissue. Conclusion Our findings demonstrate, for the first time, the potential of hPSC-derived ENS progenitors to repopulate and restore functional responses in human HSCR patient colonic tissue.

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The epigenetic regulator BAP1 is required before birth for differentiation and maintenance of the postnatal enteric nervous system in mice.

Project description:Epigenetic regulatory mechanisms are underappreciated but critical for enteric nervous system (ENS) development and maintenance. We discovered that fetal loss of the epigenetic regulator Bap1 in the ENS lineage causes severe postnatal bowel dysfunction and early death in Tyrosinase-Cre; Bap1fl/fl mice. Bap1-depleted ENS appears normal in neonates, however, by postnatal day 15 (P15), Bap1-deficient enteric neurons are largely absent from the small and large intestine of Tyrosinase-Cre; Bap1fl/fl mice. Bowel motility becomes markedly abnormal with disproportionate loss of cholinergic neurons. Single-cell RNA sequencing at P5 shows that fetal Bap1 loss inTyrosinase-Cre; Bap1fl/fl mice markedly alters the composition and relative proportions of enteric neuron subtypes. In contrast, postnatal deletion of Bap1 did not cause enteric neuron loss or impaired bowel motility. These findings suggest that BAP1 is critical for postnatal enteric neuron differentiation and for enteric neuron survival.

2024-04-01 | GSE242001 | GEO

Ret loss-of-function decreases neural crest progenitor proliferation and restricts developmental fate potential during enteric nervous system development

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

Expression data from embryonic day 17 (E17) enteric neural crest-dervied cells (ENCDC) and non-ENCDC

Project description:During the later stages of enteric nervous system (ENS) development, enteric neural crest derived cells (ENCDC) that have colonized the bowel must complete differentiating and mature into neurons and glia. This process is controlled by a complex array of intrinsic and extrinsic factors. We used microarrays to dermine which genes were differntially expressed in ENCDC versus other cells in the developing bowel. We identified many geness enriched in ENCDC with potential roles in the later stages of ENS development

2018-10-09 | GSE120936 | GEO

TMT-based quantitative analysis of brain whole proteome of miR-137 mouse models

Project description:Recent genetic evidence has revealed microRNA-137 (miR-137) as a risk gene in schizophrenia and autism spectrum disorder (ASD), and the following cellular studies have demonstrated the importance of miR-137 in regulating neurogenesis. We have generated miR-137 knockout mice which display behaviors that resemble some symptoms of these two diseases. To investigate the underlying molecular mechanism, we performed comprehensive analyses of the entire RNA and protein molecules of the miR-137 mouse brains. The dataset uploaded here is the raw data of the mass spectrometry-based whole proteome analysis of the six miR-137 mouse brains: wild-type, heterozygous (miR-137+/–) and homozygous (miR-137–/–) from two different litters. The tandem mass tag (TMT) methodology was employed in this proteomics analysis for the quantitation. The sample channels are: 128C (miR-137+/+, litter 1), 129N (miR-137+/–, litter 1), 129C (miR-137–/–, litter 1), 130N (miR-137+/+, litter 2), 130C (miR-137+/–, litter 2), and 131N (miR-137–/–, litter 2).

2018-10-17 | PXD003874 | Pride

Glial Guidance Drives Postnatal Intestinal Reinnervation by Enteric Neurons

Project description:This study investigates the phenomenon of postnatal plasticity within the enteric nervous system (ENS), specifically investigating the reinnervation potential of post-mitotic enteric neurons. Employing BAF53b-Cre for selective tracing, the reinnervation capabilities of postnatal enteric neurons in multiple model systems are shown. Denervated enteric neurons exhibit the ability to regenerate neurites in vitro, with neurite complexity and direction notably influenced by contact with enteric glial cells (EGCs). In vivo nerve fibers from transplanted enteric neurons exclusively interface with EGCs. Resident EGCs are sustained after Cre dependent ablation of enteric neurons and govern the architecture of the ENS by reinnervating enteric neurons. Transplantation experiments underscore the swift reintegration and reinnervation potential of post-mitotic neurons, leading to restored muscle function within two weeks. Optogenetic investigations further delineate time-dependent functional recovery via transplantation of isolated enteric ganglia. These revelations demonstrate the structural and functional reinnervation capacity of post-mitotic enteric neurons, underscored by EGC guidance.

2024-07-16 | GSE242208 | GEO

RNA Seq analysis of E9.5 embryonic vagal regions in Rdh10 mutants of mouse

Project description:The enteric nervous system (ENS) is formed from vagal neural crest cells (NCC), which generate the neurons and glia that regulate gastrointestinal function. Defects in the migration, colonization or differentiation of NCC in the gut can result in gastrointestinal disorders such as Hirschsprung disease (HSCR). Although mutations in many genes have been associated with the etiology of HSCR, a significant proportion of affected individuals have an unknown genetic diagnosis. Therefore, it’s important to identify new genes, modifiers and environmental factors that regulate ENS development and HSCR. We discovered that retinol dehydrogenase 10 (Rdh10) loss-of-function mouse embryos exhibit total intestinal aganglionosis, the most severe form of HSCR. Rdh10 catalyzes the first oxidative step in the metabolism of vitamin A to its active metabolite, RA, and is therefore a central regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. Rdh10 is highly expressed in the mesenchyme surrounding the entrance to the foregut and we demonstrate that paracrine retinoid signaling is essential between E7.5-E9.5 for NCC entry into the gut. Vagal NCC form and migrate in Rdh10 mutant embryos but fail to enter the foregut. Comparative RNA-sequencing revealed Ret-Gdnf-Gfra1-signaling which is critical for vagal NCC chemotaxis is downregulated in Rdh10 mutants and furthermore that the composition of the extracellular matrix through which NCC migrate is altered, particularly by increased collagen deposition. Collectively this restricts NCC entry into the gut, demonstrating that Rdh10-mediated vitamin A metabolism and RA signaling pleiotropically regulates the NCC microenvironment during ENS formation and in the pathogenesis of HSCR.

2022-02-01 | GSE166625 | GEO

Gene expression signatures in a human bladder cancer cell line SW780 transfected with miR-137 precursor molecule

Project description:To clarify the effect of miRNAs, we carried out a gene expression microarray analysis of SW780 cells transfected with a miR-137 precursor or a negative control. We found that 1,326 probe sets (1,016 unique genes) were downregulated (>2-fold) by ectopic miR-137 expression, including the previously reported miR-137 target genes CDK6, CDC42 and AURKA. Moreover, Gene Ontology analysis revealed that genes related to the cell cycle were significantly enriched among the affected genes. SW780 cells were transfected with a Pre-miR-137 miRNA Precursor Molecule (Ambion) or Pre-miR miRNA Molecules Negative Control #1 (Ambion). Forty-eight hours after transfection, total RNA extraction was carried out, and gene expression signatures were analyzed.

2012-12-01 | E-GEOD-41760 | biostudies-arrayexpress

A complementary study pipeline unravels novel players in the pathoetiology of Hirschsprung's disease

Project description:Purpose: Hirschsprung’s disease (HSCR, OMIM 142623) represents one of the main causes of neonatal intestinal obstruction. It is caused by dysfunction of neural crest cells (NCCs) and their progeny during development of the enteric nervous system (ENS). HSCR is considered a multifactorial disorder, however, associated risk genes only account for a minority of cases. Consequently, defining disease-relevant variants is still a demanding task. Methods: To reduce the number of candidate genes identified by Whole Exome Sequencing (WES) and to examine their disease-causing relevance, we established a complementary study pipeline including transcriptome data of murine embryonic ENS-relevant tissues, literature and database searches, in silico network analyses as well as functional assays using genome-edited candidate-specific cell clones. Results: Applying this strategy on a pilot set of two HSCR patients and their non-affected parents led to the identification of four novel HSCR candidate genes: ATP7A, SREBF1, ABCD1 and PIAS2. This candidate gene selection was corroborated by the discovery of further rare variants in additional HSCR cases. Moreover, expression analyses revealed that all four genes are expressed in embryonic murine gastrointestinal tissues. Functional analyses using candidate gene-specific, neuronal-like CRISPR/Cas9-edited knockout cell clones demonstrated impaired differentiation, proliferation and/or cell survival capacity. Conclusions: Taken together, the presented study pipeline was proven to be suitable for the selection and validation of candidate genes as well as to gain insight into underlying pathomechanisms of HSCR.

2020-10-12 | GSE144442 | GEO

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