Deciphering Gene Expression Program of MAP3K1 in Mouse Eyelid Morphogenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Jing Chen
PROVIDER: E-GEOD-39240 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Embryonic eyelid closure is a critical step of mammalian ocular surface development involving the forward movement and ultimate fusion of the upper and lower eyelids. Although its underlying mechanism of action is not fully understood, a functional mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is essentially required for eyelid closure. We used microarray to characterize the central role that MAP3K1 plays in embryonic eyelid closure.
2012-09-01 | GSE39240 | GEO
Project description:Mitogen-Activated Protein 3 Kinase 1 (MAP3K1) is a dynamic signaling molecule with myriad cell-type specific functions not yet fully understood. Here we describe a role of MAP3K1 in the development of female reproductive tract (FRT). MAP3K1 kinase domain deficient females (Map3k1ΔKD) exhibit imperforate vagina, labor failure and sterility. The defects correspond to shunted Müllerian duct (MD), precursor of the FRT, in embryos, and contorted caudal vagina and abrogated vagina-urogenital sinus fusion in newborns. Although MAP3K1 acts through JNK and ERK to activate WNT in epithelial cells, it is dispensable for epithelial but crucial for mesenchymal WNT activity at the caudal embryonic MD in vivo. Moreover, conditional media derived from MAP3K1-compentent, but not -deficient, epithelial cells activate TCF-luciferase reporter in fibroblasts, suggesting MAP3K1 induces secreted activators from epithelial cells to activate WNT in fibroblasts. Correspondingly, the expression of Wnt7b is high in wild type, but low in Map3k1 knockout caudal MD epithelium and MAP3K1-deficient keratinocytes. Our data reveal a temporal-spatial paracrine MAP3K1-WNT crosstalk in the regulation of caudal MD elongation and FRT development.
2024-03-22 | GSE237130 | GEO
Project description:The mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1), also known as MAP3K1, mediates activin B (ActB) signals required for eyelid epithelium morphogenesis during mouse fetal development. The present study investigates the role of MEKK1 in epithelial wound healing, another activin-regulated biological process. In a skin wound model, injury markedly stimulates MEKK1 expression and activity, which are in turn required for the expression of genes involved in extracellular matrix (ECM) homeostasis. MEKK1 ablation or down-regulation by interfering RNA significantly delays skin wound closure and impairs activation of Jun NH2-terminal kinases, induction of plasminogen activator inhibitor (PAI)-1, and restoration of cell-cell junctions of the wounded epidermis. Conversely, expression of wild-type MEKK1 accelerates reepithelialization of full-thickness skin and corneal debridement wounds by mechanisms involving epithelial cell migration, a cell function that is partially abolished by neutralizing antibodies for PAI-1 and metalloproteinase III. Our data suggest that MEKK1 transmits wound signals, leading to the transcriptional activation of genes involved in ECM homeostasis, epithelial cell migration, and wound reepithelialization.
2022-07-13 | GSE201823 | GEO
Project description:Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the most common type of breast cancer, is facing challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2- breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of HR+/HER2- breast cancer patients (n = 351) and revealed that HR+/HER2- breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2- breast cancer was related to MAP3K1 mutation and we validated experimentally that MAP3K1 mutation could attenuate CD8+ T cell-mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I-mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNAs, thereby driving tumor immune escape. In preclinical models, the postbiotics tyramine could reverse the MAP3K1 mutation-induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy.
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Project description:Mapks are regulators of T cell proliferative expansion and cell cycle progression. Genetic analysis of Th17 cells in Map3k1ÎKD and control mice will demonstrate whether Mekk1 (encoded by Map3k1) signaling activates Jnks to regulate cell cycle molecules and proliferative expansion. Comparative transcriptional profiling of Th17 molecular expression between experimental and control genotypes will reveal molecular targets that could play a role in the Map3k1-dependent mechanisms underlying proliferation.
2016-08-31 | E-MTAB-4499 | biostudies-arrayexpress
Project description:TMPRSS2 is an androgen-regulated cell surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastasis. Through the generation of mouse models with a targeted deletion of Tmprss2, we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-Met receptor tyrosine kinase signaling, and initiated a pro-invasive EMT phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo. Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment. Custom mouse cDNA microarrays were used to measure transcript levels in microdissected anterior prostate tumors from Tmprss2+/+;TRAMP mice, Tmprss2-/-;TRAMP mice or strain-matched benign epithelium. All samples were laser-capture microdissected and total RNA isolated and amplified prior to hybridization against a reference pool of normal adult mouse tissues.
2014-09-09 | E-GEOD-58822 | biostudies-arrayexpress
Project description:Transcriptional profiling of gene expression of embryonic stem cells from mutant Map3k1 mice in comparison to control EL14 cells. The differential expression of specific genes between the mutant and control groups generated from the microarray will give an idea of the molecular mechanisms regulating MAPK signaling in embryonic stem cells.
2014-06-01 | E-MTAB-1679 | biostudies-arrayexpress
Project description:Deciphering Gene Expression Program of MAP3K1 in Mouse Eyelid Morphogenesis
| PRJNA170306 | ENA
Project description:EGR1 is an early growth response zinc finger transcription factor with broad actions, including in differentiation, mitogenesis, tumor suppression, and neuronal plasticity. Here we demonstrate that Egr1-/- C57BL/6-background mice have normal eyelid development, but back-crossing to BALB/c background for 4-5 generations resulted in defective eyelid development by embryonic day E15.5, at which time EGR1 was expressed in eyelids of WT mice. Defective eyelid formation correlated with profound ocular anomalies evident by post-natal days 1-4, including severe cryptophthalmos, microphthalmia or anophthalmia, retinal dysplasia, keratitis, corneal neovascularization, cataracts, and calcification. The BALB/c albino phenotype-associated Tyrc tyrosinase mutation appeared to contribute to the phenotype, as crossing the independent Tyrc-2J allele to Egr1-/- C57BL/6 mice also produced ocular abnormalities, albeit less severe than those in Egr1-/- BALB/c mice. Thus, EGR1 in a genetic background-dependent manner plays a critical role in mammalian eyelid development and closure, with subsequent impact on ocular integrity.
2017-07-30 | GSE100690 | GEO
Project description:Purpose: Due to the rarity of Merkel Cell Carcinoma (MCC), prospective clinical trials have not been practical. This study seeks to identify biomarkers to differentiate between patients with a good and poor prognosis. Methods: Patients were stratified into good, moderate or poor prognosis. Merkel cell carcinoma (MCC) patients were stratified into one of three groups based upon status 24 months following treatment. Poor prognosis patients either presented with or progressed to distant metastasis. Patients with favorable prognosis had local disease presentation with no subsequent recurrence or nodal disease at presentation with no progression during follow-up of longer than 24 months. Moderate prognosis had recurrent local disease, development of nodal metastasis, or nodal disease at presentation with no progression during follow-up of fewer than 24 months. Using ArcturusXT Laser Capture Microdissection (Molecular Devices), tumor cells were isolated from the specific areas of interest. The captured tumor tissue was subjected to RNA extraction using the Invitrogen PureLinkM-bM-^DM-" FFPE RNA Isolation Kit. The extracted RNA was analyzed for integrity with the Agilent Bioanalyzer then amplified and hybridized to Affymetrix GeneChip Human Exon 1.0 ST arrays using the NuGEN WT- OvationM-bM-^DM-" FFPE System. Results: A total of 191 genes showed significant differential expression (pM-bM-^IM-$0.05 and 1.5-fold cutoff) between the different between the good and poor prognosis groups. Keratin 20 (KRT20) and Neurofilament protein (NEFM) have been identified in previous studies as proteins of interest in MCC. Our study showed these genes to be significantly upregulated in patients with a poor prognosis. Of interest, phospholipase A2, group X was upregulated in poor responders. Phospholipases liberate arachidonic acid from cellular membranes which can be metabolized to eicosanoids through three major pathways: the cyclooxygenase (COX), the lipoxygenase (LOX) and the cytochrome P450 monooxygenase pathways. This pathway has been implicated in several cancers. Conclusions: The study identified genes with a previous association with MCC as well as some novel genes. These genes provide the basis for further research into possible biomarkers that will enable the differentiation between patients with a good and poor prognosis. Using laser capture microdissection, tumor cells of patients with a good (n=5), moderate (n=3), and poor prognosis (n=7) were isolated from paraffin embedded archival tissue of 15 patients with Merkel cell carcinoma. Affymetrix Human Exon 1.0ST microarrays were utilized to compare gene expression signatures from good and poor prognosis patients.
2014-02-20 | E-GEOD-36150 | biostudies-arrayexpress