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Gene expression from tuft cells under scopolamine treatment

ABSTRACT: In our study, we investigated the effect of muscarinic receptor blockade on murine intestinal stem cell activity and differentiation. Following pharmacologic (scopolamine) and genetic muscarinic receptor interruption (M3R-KO, M1R-KO; Vil-Cre x M3R fl/fl, Vil-Cre x M1R fl/fl mice, respectively), we observe a selective, significant expansion of DCLK1-positive tuft cells. This is primarily sensed by endocrine Prox1-positive cells (Prox1-CreERT2 x M3R fl/fl mice), while Lgr5-positive ISCs respond with a reduction of their cellular activity (Lgr5-EGFP-IRES-CreERT2 x M3R fl/fl mice). To characterize expanding tuft cells in more detail, adult BAC transgenic DCLK1-DTR-ZSgreen reporter mice generated in our lab were treated with scopolamine or sodium chloride as controls (Sham) for 7d and live jejunal EPC-positive/ZSgreen-positive cells sorted. Extracted total RNA from sorted ZSgreen-positive cells of scopolamine- and sham-treated mice was sequenced. Further analysis revealed that expanding tuft cells orchestrate an increase in mucosal acetylcholine, which maintained intracellular signaling pathways such as p-ERK/ERK 1/2 or TCF-1/7. Finally, acute irradiation injury was employed to investigate the importance of this regulatory circuit for tissue homeostasis. Indeed, tissue injury in Vil-Cre x M3R fl/fl mice resulted in a severe reduction of epithelial DCLK1-positive tuft cells, concomitant to reduced mucosal Ach levels as well as intracellular PI3K-/p-ERK levels. Therefore, DCLK1-positive tuft cells appear essential for the maintenance of a regular intestinal cholinergic niche.

ORGANISM(S): Mus musculus

PROVIDER: GSE138365 | GEO | 2019/11/01

REPOSITORIES: GEO

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Single nucleus sequecing data of MCH neurons [scRNA-seq]

Project description:In order to understand heterogeneity of MCH neurons, by using MCH-Cre dependent ZsGreen (fl/fl) reporter mice, we isolated nuclear from 16 hypothalami of 16 mice at the age of 16-18weeks. Through flow cytometry, we were able to distinguish ZsGreen positive nuclei, and collected puried MCH nuclei in suspension. Those nuclei suspension were subjected to single cell sequence by 10x™ GemCode™ Technology for further single nuleus mRNA analysis and unravel subclusters of MCH neurons

2020-05-07 | GSE146020 | GEO

Lgr5+tuft marker+ intestinal tumor cells

Project description:We previously identified Dclk1, a tuft cell marker, marks tumor stem cells (TSCs) in mouse intestinal tumors. In this study, we have identified IL17RB as a cell surface marker distinctively expressed by Dclk1+ tuft-like tumor cells in mouse intestinal tumors. Using this tuft cell marker, we compared and analyzed the transcriptome of Lgr5-tuft marker-, Lgr5+tuft marker-, Lgr5-tuft marker+, and Lgr5+tuft marker+ tumor cells. These analyses revealed that tuft-like tumor cells in the intestinal tumors comprise two distinct subsets: highly differentiated tuft-like tumor cells (Lgr5-tuft marker+ cells) and tuft-like tumor cells with TCS potential (Lgr5+tuft marker+ cells).

2021-02-19 | GSE118853 | GEO

Single-cell RNA Sequencing (scRNA−seq) Identifies L1CAM as a Key Mediator between Epithelial Tuft Cell and Innate Lymphoid Cell in the Colon of Hnrnp I Knockout Mice

Project description:(1) Background: Knockout (KO) of heterogeneous nuclear ribonucleoprotein I (Hnrnp I) in mouse intestinal epithelial cells (IECs) induced a severe inflammatory response in the colon, followed by hyperproliferation. This study aimed to investigate the epithelial lineage dynamics and cell–cell communications that underlie inflammation and colitis. (2) Methods: Single cells were isolated from the colons of wildtype (WT) and KO mice and used in scRNA−seq. Whole colons were collected for immunofluorescence staining and cytokine assays. (3) Results: from scRNA−seq, the number of DCLK1 + colonic tuft cells was significantly higher in the Hnrnp I KO mice compared to the WT mice. This was confirmed by immunofluorescent staining of DCLK1. The DCLK1 + colonic tuft cells in KO mice developed unique communications with lymphocytes via interactions between surface L1 cell adhesion molecule (L1CAM) and integrins. In the KO mice colons, a significantly elevated level of inflammatory cytokines IL4, IL6, and IL13 were observed, which marks type−2 immune responses directed by group 2 innate lymphoid cells (ILC2s). (4) Conclusions: This study demonstrates one critical cellular function of colonic tuft cells, which facilitates type−2 immune responses by com-municating with ILC2s via the L1CAM–integrins interaction. This communication promotes pro−inflammatory signaling pathways in ILC2, leading to the increased secretion of inflammatory cytokines.

2023-10-14 | GSE245188 | GEO

Identification of genes enriched in Nkx2-1-positive neurons in the Arc, VMH, and DMH of adult mice

Project description:We aimed to identify genes enriched in Nkx2-1-positive neurons in the dorsomedial hypothalamus (DMH). Using Nkx2-1-CreERT2 mice crossed with Rosa-ZsGreen mice after tamoxifen induction, we collected ZsGreen-marked Nkx2-1-positive neurons from the DMH, ventromedial hypothalamic nucleus (VMH), and arcuate nucleus (Arc) by laser microdissection and compared their gene expression profiles.

2024-01-08 | GSE224543 | GEO

Spatial transcriptomic studies of the colon from a wildtype mouse

Project description:Transcriptomic analysis of the colon from a wildtype 8 week old female mice in C57BL6 background. In particular, we characterized the expression of genes encoding known receptors for Regenerating islet-derived proteins (REG3III) among the different colonic intestinal epithelial cell subsets under steady state. Colonic DCLK1+ tuft cell-containing spots had the highest expression levels of genes encoding various REG3III receptors.

2023-12-31 | GSE210973 | GEO

mRNA transcriptome sequencing of wild type (WT) and intestinal epithelial cell specific Axin1 Knockout mice (Axin1KOΔIEC) that have udergone DSS-induced colitis and AOM/DSS-induced colorectal tumorigenesis

Project description:Purpose : The goals of this study are to compare NGS-derived transcriptome profiling (RNA-seq) of colon samples of intestinal epithelial cell specific Axin1 Knockout mice and WT controls that were submitted to DSS-induced colitis and AOM/DSS-induced colorectal carcinogenesis. Methods : DSS-induced colitis was performed on Axin1flfl (WT) and Vil CreERT2;Axin1fl/fl (Axin1KOΔIEC) mice by giving 3% DSS dissolved in drinking water for 7 days and subsequently placed on regular water for recovery before sacrifice at Day 7 and D13. Methods : AOM/DSS-induced colorectal tumorigenesis was performed on Axin1flfl (WT) and Vil CreERT2;Axin1fl/fl (Axin1KOΔIEC) mice that were sacrificed at day 100 post-AOM injection to collect colorectal tumors. Methods : Colonic mRNA profiles of WT and Axin1KOΔIEC mice were generated by deep sequencing using Illumina NextSeq 500 instrument (150base-lengths read V2 chemistry in a paired-end mode)

2022-02-09 | GSE196220 | GEO

A nasal cell atlas reveals heterogeneity of tuft cells and their role in directing olfactory stem cell proliferation

Project description:The olfactory neuroepithelium serves as a sensory organ for odors and forms part of the nasal mucosal barrier. Olfactory sensory neurons are surrounded and supported by epithelial cells. Among them, microvillous cells (MVCs) are strategically positioned at the apical surface, but their specific functions are enigmatic and their relationship to the other specialized epithelial cells, particularly the solitary chemosensory cell family, is unclear. Here, we establish that the family of MVCs comprises tuft cells and ionocytes in both mice and humans. Integrating analysis of the respiratory and olfactory epithelia, we define the unique receptor expression of TRPM5+ tuft-MVCs compared to Gɑ-gustducinhigh respiratory tuft cells and characterize a new population of glandular DCLK1+ tuft cells. To establish how allergen sensing by tuft-MVCs might direct olfactory mucosal responses, we employed an integrated single-cell transcriptional and protein analysis. Inhalation of Alternaria induced mucosal epithelial effector molecules including Chil4, and a distinct pathway leading to proliferation of the quiescent olfactory horizontal basal stem cell (HBC) pool, both triggered in the absence of olfactory apoptosis. While the Chil4 pathway was dependent on STAT6 signaling and innate lymphocytes, neither were required for HBC proliferation. Alternaria- and ATP- elicited HBC proliferation was dependent on tuft-MVCs, establishing these specialized epithelial cells as regulators of olfactory stem cell responses. Together our data provide high resolution characterization of nasal tuft cell heterogeneity and uncover a novel function for TRPM5+ tuft-MVCs in directing the olfactory mucosal response to allergens.

2023-12-04 | GSE245074 | GEO

Adult enteric Dclk1-positive glial and neuronal cells reveal distinct responses to acute intestinal injury

Project description:Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment, and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. While Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom+/CD49b+ glial-like and Dclk1-tdTom+/CD49b- neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time, yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom+ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom+/CD49b+ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom+/CD49b- neuronal cell types. Finally, subsets of Dclk1-tdTom+/CD49b+ glial-like cells demonstrate prominent overlap with Nestin and p75NTR, and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural-crest like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage.

2021-10-31 | GSE156031 | GEO

Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses

Project description:Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified up-regulated DCLK1 in macrophages in atherosclerotic lesions of ApoE-/- mice fed an HFD and determined that macrophage-specific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL-induced inflammation via NF-κB signaling pathway in primary macrophages. Co-immunoprecipitation followed by LC-MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF-κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF-κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis.

2023-02-27 | PXD039083 | Pride

Proteomic of huh7 grown in normal and glucose-deficient conditions

Project description:Tumor cell metabolic plasticity is essential for tumor progression and therapeutic response, but the mechanism for regulation of metabolic plasticity remain poorly explored. Here, we identify PROX1 as an essential determinant for tumor metabolic plasticity. Notably, PROX1 is significantly reduced in response to metabolic stress or AMPK activation and is elevated in LKB1-deficient tumors in mice and human. Furthermore, the Ser79 phosphorylation of PROX1 by AMPK significantly alters its protein activity and allows a rapid recruitment of CUL4-DDB1 E3 ubiquitin ligase to promote PROX1 degradation under glucose starvation, a critical event that drives BCAA metabolism rewiring to suppress mTOR signaling. Importantly, PROX1 loss or Ser79 phosphorylation in HCC shows therapeutic resistance to metformin. Consistently, genetic ablation of PROX1 renders LKB1‐deficient KRAS-driven lung cancer resistant to phenformin treatment. Conversely, mice harboring non-phosphorylated PROX1 mutant or LKB1 mutant exhibit high PROX1 stabilization, promoting liver and lung cancer progression. Clinically, AMPK-PROX1 axis in human cancers is important for patient clinical outcomes. Collectively, our results demonstrate that the deficiency in the LKB1-AMPK axis in cancers reactivates PROX1 to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling, and facilitating tumorigenesis and aggressiveness.

2022-09-27 | PXD036977 | Pride

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