Lysophosphatidic acid treatment improves brush border maturation and apical SGLT1 activity in Myo5b deficient mice, a model of MVID
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ABSTRACT:
PROVIDER: PRJNA579150 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10336729_1.fastq.gz | Fastqsanger.gz | |||
| SRR10336729_2.fastq.gz | Fastqsanger.gz | |||
| SRR10336730_1.fastq.gz | Fastqsanger.gz | |||
| SRR10336730_2.fastq.gz | Fastqsanger.gz | |||
| SRR10336731_1.fastq.gz | Fastqsanger.gz |
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Project description:Myosin Vb (Myo5b) is an essential trafficking protein for membrane recycling in gastrointestinal (GI) epithelial cells and its inactivating mutation causes the congenital diarrheal disease, microvillus inclusion disease (MVID). We previously reported that Myo5b deficiency in mice causes mislocalization of SGLT1 and NHE3, but retained apical function of CFTR, resulting in malabsorption and secretory diarrhea. Activation of lysophosphatidic acid (LPA) receptors can improve diarrhea, but the effects of LPA on MVID symptoms is unclear. We therefore tested whether LPA treatment can ameliorate the epithelial deficits in Myo5b knockout (KO) mice. Methods: Adult tamoxifen-induced, intestine-specific, Myo5b KO (VillinCreERT2;Myo5bflox/flox) and littermate control mice were treated with LPA, an LPAR2 agonist (GRI977143), or vehicle for 4 days after a single tamoxifen injection. Apical SGLT1 and CFTR activities were measured in Üssing chambers. The localization of membrane transporters was evaluated by immunostaining in mouse tissues and enteroids. RNA sequencing and enrichment analysis were performed with isolated jejunal epithelial cells. Results: Daily treatment with LPA decreased the frequency of multivesicular bodies and the expression of cathepsins, but did not affect the formation of microvillus inclusions in Myo5b KO mice. LPA partially restored the brush border height and the localization of SGLT1 and NHE3 in Myo5b KO small intestine and enteroids. SGLT1-dependent short-circuit current (Isc) was increased and abnormal CFTR activities were suppressed in LPA-treated jejunum compared to that of vehicle-treated Myo5b KO mice. Conclusions: Cell autonomous LPA signaling may modulate a Myo5b-independent trafficking mechanism and the brush border maturation, demonstrating a therapeutic potential for LPA in the treatment of MVID.
2019-10-24 | GSE139302 | GEO
Project description:Autoimmune diseases that affect the kidney proximal tubule (PT) cause proteinuria and are implicated in the pathogenesis of kidney failure. Previous evidence demonstrated that circulating anti-brush border antibodies (ABBA) target megalin (LRP2) but whether other components of the PT drive autoimmunity was unknown. Here we investigate a patient with LRP2-negative ABBA disease, and applied immunoprecipitation, mass spectrometry, and confocal imaging to identify cubilin as a novel antigen associated with the autoimmune disorder.
2023-04-06 | PXD030159 | Pride
Project description:Discovery of target antigen resulting in autoimmune form of renal interstitial nephritis using a brush border biotinylation, affinity purification of target antigen using patient sera, and characterization of biotinylated species in the immunopurified complex. Results were confirmed by IF of patient biopsies and IB using recombinant target antigen.
2017-04-04 | MSV000080885 | MassIVE
Project description:Purpose: Tracheal epithelial brush cells are rare chemosensory cells defined by their expression of elements of the bitter taste transduction system, and known to activate the cholinergic nervous system in the murine lung. Similar chemosensory cells in the intestine can generate lipid mediators and pro-inflammatory cytokines but whether brush cell can contribute to airway inflammation is unknown. Furthermore, despite the advances in understanding chemosensory cell effector functions, the receptors that mediate chemosensory cell activation and expansion beyond taste receptors in any compartment remain largely unknown. Methods: In this study, we isolated tracheal brush cells by FACS from naïve ChATBAC-eGFP mice with knockin of eGFP within a BAC spanning the acetylcholine transferase locus, marking brush cells in the epithelium and performed transcriptome profiling using low input RNA sequencing. We compared tracheal brush cells to EpCAM+ epithelial cells and CD45+ hematopoetic cells in naive mice. Results: When compared to EpCAM+ EpCs and to CD45+ cells in the airway, principal component analysis demonstrated that brush cells grouped quite distinctly. This brush cell distinction relative to EpCAM+ cells, was further reflected in the striking number of highly differentially expressed genes. This included 1305 genes expressed at 4-fold or higher levels in EpCAM+eGFP+ cells (brush cells), of which 418 genes were expressed at 32-fold or higher levels in brush cells. Conclusions: Our study represents the first detailed analysis of the transcriptome of tracheal brush cells and identifies a unique set of genes that are primarily expressed in brush cells including the bitter taste transduction system, synthenic machinery for several pro-inflammatory lipid mediators and HoxA2 transciptional factors.
2018-07-03 | GSE116525 | GEO
Project description:Carbon brush sample Genome sequencing and assembly
| PRJNA981650 | ENA
Project description:Diarrhea results from reduced net fluid and salt absorption caused by an imbalance in intestinal absorption and secretion. The bulk of sodium and water absorption in the intestine is mediated by Na(+)/H(+) exchanger 3 (NHE3), located in the luminal membrane of enterocytes. We investigated the effect of lysophosphatidic acid (LPA) on Na(+)/H(+) exchanger activity and Na(+)-dependent fluid absorption in the intestine.We analyzed the effects of LPA on fluid absorption in intestines of wild-type mice and mice deficient in Na(+)/H(+) exchanger regulatory factor 2 (NHERF2; Nherf2(-/-)) or LPA(2) (Lpa(2)(-/-)). Roles of LPA(5) and NHERF2 were determined by analysis of heterologous expression.Under basal conditions, LPA increased fluid absorption in an NHE3-dependent manner and restored the net fluid loss in a mouse model of acute diarrhea. Expression of the LPA receptor LPA(5) was necessary for LPA-induced stimulation of NHE3 activity in colonic epithelial cells. Stimulation of NHE3 by the LPA-LPA(5) signaling required coexpression of NHERF2, which interacted with LPA(5). LPA-mediated intestinal fluid absorption was impaired in Nherf2(-/-) mice, demonstrating the requirement for NHERF2 in LPA(5) activity. However, fluid absorption was unaltered in Lpa(2)(-/-) mice. LPA stimulated NHE3 and fluid absorption in part by increasing NHE3 protein abundance at the brush border membrane of intestinal epithelial cells.LPA is a potent stimulant of NHE3 and fluid absorption in the intestine, signaling through LPA(5). Regulation by LPA(5) depends on its interaction with NHERF2. LPA might be useful in the treatment of certain diarrheal diseases.
| S-EPMC2976485 | biostudies-literature
Project description:Most epithelial cells contain apical membrane structures associated to bundles of actin filaments, which constitute the brush border. Whereas microtubule participation in the maintenance of the brush border identity has been characterized, their contribution to de novo microvilli organization remained elusive. Hereby, using a cell model of individual enterocyte polarization, we found that nocodazole induced microtubule depolymerization prevented the de novo brush border formation. Microtubule participation in brush border actin organization was confirmed in polarized kidney tubule MDCK cells. We also found that centrosome, but not Golgi derived microtubules, were essential for the initial stages of brush border development. During this process, microtubule plus ends acquired an early asymmetric orientation toward the apical membrane, which clearly differs from their predominant basal orientation in mature epithelia. In addition, overexpression of the microtubule plus ends associated protein CLIP170, which regulate actin nucleation in different cell contexts, facilitated brush border formation. In combination, the present results support the participation of centrosomal microtubule plus ends in the activation of the polarized actin organization associated to brush border formation, unveiling a novel mechanism of microtubule regulation of epithelial polarity.
| S-EPMC5673559 | biostudies-literature
Project description:Intestinal epithelial cells are covered by the brush border, which consists of densely packed microvilli. The Intermicrovillar Adhesion Complex (IMAC) connects the microvilli and is required for proper organization of the brush border. The protocadherin CDHR5 is an important member of the IMAC, but it is unclear whether CDHR5 has mainly structural functions or is also involved in cellular signaling. This issue was resolved with a CDHR5 knockout mouse model. Intestinal epithelial cells were isolated from the small intestine of four wild-type and four CDHR5 knockout mice. Bulk RNA sequencing was performed to provide insight into the functions of CDHR5 in cellular signaling and gene regulation.
2023-04-13 | E-MTAB-12525 | biostudies-arrayexpress
Project description:Knockout of HNF4A in yolk sac resulted in decreased expression levels of brush border genes and increased expression levels of stress fiber genes.
2021-03-15 | GSE166125 | GEO