Expression data of mouse ENCCs and mouse embryonic Gut E14.5
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE34208 | GEO | 2011/12/07
SECONDARY ACCESSION(S): PRJNA149673
REPOSITORIES: GEO
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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. 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: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:RET/GDNF and ET3/EDNRB regulate cell survival, differentiation and migration of neural crest-derived cells. Many signalling mediators of RET have been characterized but the target genes at the end of the signalling cascade are largely unknown. Since the RET/EDNRB crosstalk has been previously shown, we used a Caenorhabditis elegans knockout strain of Nep-1, a homologue of human ECE1 (endothelin-converting enzyme-1), to identify new target genes. Transcriptome comparison between wild-type and Nep-1 strains at different stages identified vit-3 as a differentially expressed gene. Molecular studies of the vit3 mammalian homologue, Apoliporotein B (APOB), were performed in the murine Neuro2a cell line, a model of ENS development. Apob expression in Neuro2a is specifically activated by the RET/GDNF signalling pathway, since Ret silencing abolished Apob increase, and this effect is induced by MAPK P38 kinase activation. Mouse Apob promoter study revealed that there is a p53-dependent repressor element in the promoter region which blocks Apob expression and we show that actually p53 binds to this region. We demonstrated that RET/GDNF and EDNRB/endothelin 3 (ET-3) cooperate in inducing neuronal differentiation resulting in Apob activation. We also show that Apob expression is downregulated in mouse embryos homozygous for the mutation RetC620R and presenting a severe HSCR phenotype, whereas heterozygous mice, phenotypically normal, present a significant increase in Apob expression. These data suggest that Apob has an important role in RET-mediated neuronal development and APOB decrease may have an impact in human disorders where RET absence has been already identified, such as HSCR and Parkinson disease. Gene expression analysis using Affymetrix GeneChip C. elegans arrays in order to identify genes up- or down-regulated in nep-1 strains, homologue of human ECE1 (endothelin-converting enzyme 1). Comparison of the transcriptomes between wt and nep-1 strains in larval stage L3 and adult C. elegans.
2011-09-23 | E-GEOD-32339 | biostudies-arrayexpress
Project description:RET/GDNF and ET3/EDNRB regulate cell survival, differentiation and migration of neural crest-derived cells. Many signalling mediators of RET have been characterized but the target genes at the end of the signalling cascade are largely unknown. Since the RET/EDNRB crosstalk has been previously shown, we used a Caenorhabditis elegans knockout strain of Nep-1, a homologue of human ECE1 (endothelin-converting enzyme-1), to identify new target genes. Transcriptome comparison between wild-type and Nep-1 strains at different stages identified vit-3 as a differentially expressed gene. Molecular studies of the vit3 mammalian homologue, Apoliporotein B (APOB), were performed in the murine Neuro2a cell line, a model of ENS development. Apob expression in Neuro2a is specifically activated by the RET/GDNF signalling pathway, since Ret silencing abolished Apob increase, and this effect is induced by MAPK P38 kinase activation. Mouse Apob promoter study revealed that there is a p53-dependent repressor element in the promoter region which blocks Apob expression and we show that actually p53 binds to this region. We demonstrated that RET/GDNF and EDNRB/endothelin 3 (ET-3) cooperate in inducing neuronal differentiation resulting in Apob activation. We also show that Apob expression is downregulated in mouse embryos homozygous for the mutation RetC620R and presenting a severe HSCR phenotype, whereas heterozygous mice, phenotypically normal, present a significant increase in Apob expression. These data suggest that Apob has an important role in RET-mediated neuronal development and APOB decrease may have an impact in human disorders where RET absence has been already identified, such as HSCR and Parkinson disease. Gene expression analysis using Affymetrix GeneChip C. elegans arrays in order to identify genes up- or down-regulated in nep-1 strains, homologue of human ECE1 (endothelin-converting enzyme 1).
2011-09-24 | GSE32339 | GEO
Project description:During fetal development, neural crest precursors give rise to neurons of the enteric nervoussystem (ENS). However, given our evolving understanding of the dynamic nature of the ENS, itis not clear whether this developmental paradigm holds true at different post-natal stages. Here,we show that due to loss of GDNF-RET signaling with age, neural crest-derived neurons un-dergo a progressive decline in numbers. They are replaced by neurons derived from the embry-onic mesoderm which, with increasing age, become the dominant form of neurons in the ENS,and this is associated with functional deficits in intestinal motility. Using single cell transcrip-tomics and immunochemical approaches, we characterize these mesoderm-derived neuronsand show that this novel lineage of neurons expresses MET and is dependent on HGF for itsexpansion. Normal intestinal function in the adult gastrointestinal tract therefore appears to re-quire an optimal balance between these two distinct lineages within the ENS.
2021-04-30 | GSE156146 | GEO
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
Project description:The enteric nervous system (ENS), which is derived from enteric neural crest cells (ENCCs) during gut development, represents the neuronal innervation of the gastrointestinal tract and is critical for regulating normal intestinal function. Compromised ENCC migration can lead to Hirschsprung Disease, which is characterized by an aganglionic distal bowel. We find that removal of the ceca, a paired structure present at the midgut-hindgut junction in avian intestine, leads to severe hindgut aganglionosis, suggesting that the ceca are required for ENS development. To test this, we replaced the ceca of embryonic day 6 (E6) wild-type chicks with ceca from transgenic GFP chicks. Interestingly, the entire hindgut ENS arises from the GFP+ ceca-derived ENCC population. Comparative transcriptome profiling of the cecal buds compared to the interceca region shows that the non-canonical Wnt signaling pathway is preferentially expressed within the ceca. Specifically, Wnt11 is highly expressed in the ceca, as confirmed by RNA in situ hybridization, leading us to hypothesize that cecal expression of Wnt11 is important for ENCC colonization of the hindgut. Organ cultures were prepared using E6 avian intestine, when ENCCs are migrating through the ceca, and showed that Wnt11 inhibits enteric neuronal differentiation. These results reveal an essential role for the ceca during hindgut ENS formation and highlight an important function for non-canonical Wnt signaling in regulating ENCC differentiation and thereby promoting their migration into the colon.
2021-11-01 | GSE182783 | GEO
Project description:To better understand the signaling and transcriptional events involved in the GDNF-independent emergence of the ureteric bud from the Wolffian duct, microarray expression analysis was performed on embryonic kidneys from wild-type and Ret-deficient mice. Microarray data was used to identify genes and gene networks involved in the GDNF-independent outgrowth of the ureteric bud. Whole embryonic kidneys from E12.5 Ret mutant and wild-type mice were isolated. Isolated kidneys were lysed and RNA was extracted with the Qiagen RNEasy Micro kit. The RNA was amplified using the NuGEn Ovation kit and hybridized to the Affymetrix GeneChip Mouse Whole Genome 430 2.0 microarray. Three biological replicates for Ret-knockout and wild-type kidneys were performed.
2012-03-31 | E-GEOD-32093 | biostudies-arrayexpress
Project description:The N-Myc Downstream-Regulated Gene 4 (NDRG4), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the tumor microenvironment, we here establish different Ndrg4 knockout (Ndrg4-/-) CRC models and an in-direct co-culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that absence of Ndrg4 does not trigger any functional or morphological GI-abnormalities. However, combining in vivo, in vitro and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4-/- ENS cell secretome, which is enriched for Nidogen-1 (Nid1) and Fibulin-2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance tumorigenic capacities of CRC cells and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4, is involved in colorectal pathogenesis and that ENS-derived Nidogen-1 and Fibulin-2 enhance colorectal carcinogenesis.
2021-04-23 | PXD024502 | Pride
Project description:The molecular mechanisms of endocrine resistance in breast cancer remain poorly understood. Here we used PRO-seq to map the location of hundreds of genes and thousands of distal enhancers whose activities differ between endocrine sensitive and resistant MCF-7 cells. Our genome-wide screen identified a 16-fold transcriptional increase in glial-cell line derived neurotrophic factor (GDNF), a RET tyrosine kinase receptor ligand, which is both necessary and sufficient for resistance in MCF-7 cells. GDNF causes endocrine resistance by switching the active state of a bi-stable feedback loop from ERα signaling to GDNF-RET signaling. To catalyze this switch, we found that GDNF directly downregulates ERα transcription and activates the transcription factor EGR1, which, in turn, induces GDNF expression. Remarkably, both MCF-7 cells and ER+ primary tumors appear poised for endocrine resistance via the RET signaling pathway, but lack robust RET ligand expression and only develop resistance upon expression of GDNF or other RET ligands.
2018-02-22 | GSE93229 | GEO