Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA287847 | ENA |
REPOSITORIES: ENA
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Project description:Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated mice (cGrp78f/f) with lung epithelial cell-specific knockout (KO) of Grp78, a gene encoding the ER chaperone 78-kDa glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78f/f pups died immediately after birth, likely due to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-β (TGF-β)/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress and TGF-β/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone taursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78f/f lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress and suggest the UPR as a potential therapeutic target in BPD. Whole-genome expression profiling was performed using MouseRef-8 v2.0 Expression BeadChips (Illumina) on RNA isolated from lungs of four Grp78f/f and three cGrp78f/f mice at E18.
2016-01-15 | E-GEOD-70208 | biostudies-arrayexpress
Project description:Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated mice (cGrp78f/f) with lung epithelial cell-specific knockout (KO) of Grp78, a gene encoding the ER chaperone 78-kDa glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78f/f pups died immediately after birth, likely due to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-β (TGF-β)/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress and TGF-β/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone taursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78f/f lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress and suggest the UPR as a potential therapeutic target in BPD.
2016-01-15 | GSE70208 | GEO
Project description:Endoplasmic reticulum (ER) stress is a cause of beta cell death in both T1D and T2D. However, no therapeutics to reduce beta cell death have been approved, in part because molecular mechanisms driving beta cell death during ER stress are insufficiently defined. GRP78, an ER chaperone, is the critical regulator of unfolded protein response (UPR) stress response pathways. GRP78 binds and suppresses UPR initiators during the unstressed state, releasing them to promote UPR activation during stress. To study pathways causing beta cell decompensation during active ER stress and the related stress response, we engineered mice genetically lacking GRP78 in pancreatic beta cells. GRP78 deletion caused acute insulin deficient diabetes in pups before weaning, with reduced beta cell mass due to increased apoptosis. Molecular studies identified deregulated UPR, specifically IRE1 activity, as driving cell death. Unbiased and targeted analyses outline a pathway in which JNK activity downstream of IRE1 kinase leads to p53 activation to mediate beta cell death during ER stress. Remarkably, in vivo JNK inhibition reduced beta cell death in two distinct ER stress diabetes models. In human beta cells, inhibitors of JNK and of p53 were both effective to improve beta cell survival in the face of ER stress. Our findings provide insight into mechanisms causing beta cell death and outline possible therapeutic targets to preserve insulin secretory capacity in the face of ER stress.
2026-05-27 | GSE282680 | GEO
Project description:Sin3a regulates epithelial progenitor cell fate during lung development
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Project description:Wnt/β-catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/β-catenin signaling promotes tissue repair in emphysema, a devastating lung disease with progressive loss of parenchymal lung tissue. The identity of Wnt/β-catenin responsive progenitor cells and the potential impact of Wnt/β-catenin signaling on adult distal lung epithelial progenitor cell function in emphysema, are poorly understood. Here, we used a TCF/Lef:H2B/GFP reporter mice to investigate the role of Wnt/β-catenin signaling in lung organoid formation. We identified an organoid-forming adult distal lung epithelial progenitor cell population characterized by a low Wnt/β-catenin activity, which was enriched in club and alveolar epithelial type (AT)II cells. To further characterize the lung epithelial populations with different Wnt activities, we perform microarray analysis using freshly isolated Wnthigh/low/negative lung epithelial cells to study their transcriptome, specially the enriched genes and signaling pathways in the Wnt low population related epithelial stem cell functions.
2020-06-12 | GSE150957 | GEO
Project description:Bone morphogenetic protein 4 (BMP4) is essential for lung development. To define its intracellular signaling mechanisms by which BMP4 regulates lung development, BMP-specific Smad1 or Smad5 was selectively knocked out in fetal mouse lung epithelial cells. Abrogation of lung epithelial-specific Smad1, but not Smad5, resulted in retardation of lung branching morphogenesis and reduced sacculation, accompanied by altered distal lung epithelial cell proliferation and differentiation, and consequently severe neonatal respiratory failure. By combining cDNA microarray with ChIP-chip analyses, Wnt inhibitory factor-1 (Wif1) was identified as a novel target gene of Smad1 in the developing mouse lung epithelial cells. Loss of Smad1 transcriptional activation of Wif1 expression was associated with reduced Wif1 expression and increased Wnt/beta-catenin signaling activity in lung epithelia, resulting in specific fetal lung abnormalities. Therefore, a novel regulatory loop of BMP4-Smad1-Wif1-Wnt/beta-catenin in coordinating BMP and Wnt pathways to control fetal lung development is suggested. mRNA profiling: Total RNA was isolated from left lobe lungs of three pair of E18.5 wild type and Smad1 lung epithelium-specific conditional knockout mice
2011-01-07 | E-GEOD-26502 | biostudies-arrayexpress
Project description:Mammalian lung development requires coordinated gene regulation to drive lung bud formation, branching morphogenesis, proximal-distal patterning, and epithelial specification. While key transcriptional and signaling regulators are known, the epigenetic regulators are less well studied. Here, we identify the canonical BAF complex as essential for lung epithelial development. Complete loss of BAF complex causes failure of lung formation, and selective deletion of ARID1A leads to loss of distal patterning and reduced alveolar type 1 (AT1) cell differentiation, with emergence of a highly proliferative cell state defined by joint activation of YAP and WNT signaling and loss of BMP response. Epigenomic analyses demonstrate broad failure of cell type-specific enhancer activation. Notably, exogenous BMP4 rescues distal differentiation in embryonic murine lung organoids, while YAP and WNT signaling require functional BAF complex. These data demonstrate a requirement for BAF complex activity during lung epithelial development and reveal a surprising differential specificity between signaling pathways.
2026-03-17 | GSE325094 | GEO
Project description:Gata6 regulates lung epithelial stem cell development and airway regeneration. Here, the expression profile of microRNA was investigated when Gata6 was depleted during lung development.
2011-03-01 | GSE25874 | GEO
Project description:SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development
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Project description:Foxp1/4 transcription factors are conserved transcriptional repressors expressed in overlapping patterns during lung development as well as in the adult lung. However, the role of Foxp1/4 in development and homeostasis of the pseudostratified epithelium of the proximal airways and trachea is unknown. We propose to determine the roles for Foxp1/4 in lung development by deleting these genes in lung epithelial specific knockout mice. To explore the genome wide consequences of Foxp1/4 deficiency on secretory epithelial differentiation in the lung, we performed microarray analysis of Shh- cre control and Foxp1/4ShhcreDKO mutants lungs at E14.5, 3 embryos, respectively.
2012-08-01 | E-GEOD-34584 | biostudies-arrayexpress