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Chronic AMPK inactivation slows SHH medulloblastoma progression by inhibiting mTORC1 and depleting tumor stem cell populations

ABSTRACT: We report scRNA-seq data showing the effect of Prkaa1/2 deletion on medulloblastomas that form in Smo-mutant mice. We generate tumor-bearing mice by breeding hGFAP-Cre/Prkaa1fl/fl/Prk112fl/fl and Prkaa1fl/fl/Prk112fl/fl/SmoM2 mouse lines to prodce tumor-prone progeny with homozygous, conditional deletion of Prkaa1 and Prkaa2 (G-SmoAMPK mice). We compared tumors from G-Smo mice withintact Prkaa1 and Prkaa2 to tumors from G-SmoAMPK mice, using Drop-seq-based scRNA-seq.

ORGANISM(S): Mus musculus

PROVIDER: GSE190297 | GEO | 2021/12/08

REPOSITORIES: GEO

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Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib

Project description:We report scRNA-seq data showing the effect of palbociclib treatment on medulloblastomas that form in Smo-mutant mice. We generate tumor-bearing mice by breeding hGFAP-Cre and SmoM2 mouse lines to prodce tumor-prone progeny heterozygous for both transgenes (G-Smo mice). We compare tumors from untreated G-Smo mice to tumors from G-Smo ice treated with nanoparticle--delievered palbociclib, using Drop-seq-based scRNA-seq.

2021-11-16 | GSE188672 | GEO

Gene expression profiling of constitutive activation of Smoothened in the mouse uterus

Project description:In order to gain a better understanding of Ihh action during embryo implantation, we constitutively activated Smo in the murine uterus using the PRcre mouse model (PRcre/+SmoM2+; SmoM2). Female SmoM2 mice were infertile. They exhibited normal serum progesterone levels and normal ovulation, but ova failed to be fertilized in vivo and the uterus failed to undergo the artificially induced decidual response. SmoM2 mice exhibited uterine hypertrophy. The endometrium had a reduced number of uterine glands and the endometrial stroma lost its normal morphologic characteristics. Microarray analysis of 3 month old SmoM2 uteri demonstrated a chondrocytic signature and confirmed that constitutive activation of SmoM2 increased extracellular matrix production. Thus, constitutive activation of Smo in the mouse uterus alters the extracellular matrix which interferes with early pregnancy. Keywords: two group comparison We constitutively activated Hh signaling in the uterus by the expression of a mutant SmoM2 allele. We crossed these mice to the PRcre mouse model to constitutively activate Smo in the murine uterus (PRcre/+SmoM2+; SmoM2). High density DNA microarray analysis was performed on 3 month old control and SmoM2 uteri.

2010-04-13 | E-GEOD-17263 | biostudies-arrayexpress

Gene expression profiling of constitutive activation of Smoothened in the mouse uterus

2010-04-13 | GSE17263 | GEO

An essential role for the Gai2 protein in Smoothened-stimulated mammary epithelial cell proliferation

Project description:Hedgehog (Hh) signaling is critical for organogenesis, tissue homeostasis, and stem cell maintenance. Smoothened (SMO), the primary effector of Hh signaling, is expressed ectopically in human breast cancer, as well as in other cancers. Constitutive activation of SMO in mouse mammary glands leads to paracrine stimulation of proliferation, as well as hyperplasia. In canonical signaling, SMO functions via GLI transcription factor activation. However, recent data from Drosophila and mammalian cell lines indicate that SMO can function non-canonically as a G-protein coupled receptor (GPCR) by coupling to heterotrimeric G proteins, particularly those in the pertussis toxin (PTX)-sensitive G-alpha-i (Gai) class. Whether SMO functions as a GPCR in mammalian tissues in vivo is not known. Using genetically modified mouse models, we demonstrate here that SMO-induced stimulation of proliferation is PTX sensitive, and requires Gai2, but not Gai1 or Gai3. Our findings provide evidence for a non-canonical GPCR function of activated SMO in vivo, a finding that may have clinical significance given that most SMO-targeted agents were selected based largely on their ability to block canonical GLI-mediated transcription. Primary mammary epithelial cell RNA was deep-sequenced from mT-mG/SmoM2;MMTV-Cre (EGFP), mT-mG/SmoM2;MMTV-Cre (tdTomato), and mT-mG/SmoM2;+ cells to examine the effects of SmoM2 overexpression in the mammary gland.

2015-09-08 | E-GEOD-70210 | biostudies-arrayexpress

Gene expression in mice with conditional over-activation of hedgehog signaling in the ovary

Project description:The objective of the study was to determine the cause of anovulation in transgenic mice with conditional over-activation of the hedgehog signaling pathway in the ovary. In Amhr2(cre/+)-SmoM2 transgenic mice, a constitutively active version of the hedgehog signal transducer, smoothened (SMO), known as SMOM2, is expressed in the ovary following cre-mediated recombination. The hypothesis tested is that changes in the neonatal ovary caused by over-activation of hedgehog signaling leads to the life-long anovulation phenotype in transgenic mice. Microarrays were used to examine differences in gene expression in ovaries of two day old wild-type mice (Amhr2(+/+)-SmoM2) and transgenic mice (Amhr2(cre/+)-SmoM2) in which the hedgehog signaling pathway was conditionally over-activated in the ovary. Two microarrays were performed. RNA samples were prepared from ovaries of 8 Amhr2(+/+)-SmoM2 control mice and 8 Amhr2(cre/+)-SmoM2 mutant mice on day two of age. RNA quality was assessed by measurement of ribosomal RNA on an Agilent 2100 Bioanalyzer.

2012-03-14 | E-GEOD-35123 | biostudies-arrayexpress

BMP7 expression in mammalian cortical radial glial cells increases the length of the neurogenic period

Project description:Purpose:To asses changes in gene expression profiles of single cell from the E39 Ferret Cortex. Mouse E18 littermate controls cortex, and Smo CKO (SmoF/F hGFAP-Cre) mice. Methords: E39 ferret cortex, E18 wild type and Smo CKO cortices were carefully dissected under a fluorescent stereoscope, and incubated in 4 ml of papain solution for 20 min at 37℃, The cortical tissues were gently triturated, filtered through a 40 mm strainer, and washed with HBSS to obtain the single cell suspension. The Chromium droplet-based sequencing platform (10X Genomics) was used to generate scRNA-seq libraries, following the manufacturer’s instructions. The cDNA libraries were purified, quantified using Agilent 2100 Bioanalyzer, and sequenced on the Illumina Hiseq4000 Results: E18 SmoF/F (control) cortex, 10524 cells, 1954 genes/cell; hGFAP-Cre; SmoF/F cortex, 7596 cells, 2104 genes/cell; E39 ferret cortex, 23482 cells, 1759 genes/cell.

2023-06-12 | GSE221389 | GEO

Gene expression in mice with conditional over-activation of hedgehog signaling in the ovary

2012-03-14 | GSE35123 | GEO

Mechanosensing brain tumor cells construct blood-tumor barrier to mask chemosensitivity

Project description:This dataset includes the raw single-cell RNAseq data from Math1-Cre;SmoM2 and Math1-Cre;SmoM2;Piezo2 fl/fl mouse medulloblastoma model. In this project, we focused on transcriptomic alteration caused by Piezo2 knockout in Sox2 positive MB initiation cells.

2022-09-22 | GSE197402 | GEO

Gene expression analysis of wild type and Hedgehog pathway-activated embryonic mouse stomach

Project description:The Hedgehog signaling pathway plays important roles in gut development and homeostasis. In this study, we use Affymatrix Miroarray to analyze the gene expression profiles of wild type stomach and SmoM2-expressing stomach at E13.5. The goal of this study is to understand the transcription program regulated by Hedgehog in the developing gut. SmoM2 is a constitutively active form of Smo, whick leads to Hedgehog ligand independent cell-autonomous pathway activation.

2019-07-09 | GSE103235 | GEO

The lateral cerebellum is preferentially sensitive to high sonic hedgehog signaling and medulloblastoma formation

Project description:The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location since SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened (SMO) mutations form more specifically in the hemispheres than those with Patched 1 (PTCH1) mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation of Smo (SmoM2) or loss-of-Ptch1, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres with SmoM2-mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high level SHH signaling compared to GCPs in the medial cerebellum (vermis), as more SmoM2 or Ptch1-mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene expression profiles, and found that deletion of the genes most highly expressed in the hemispheres (Nr2f2) or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide new insights into intrinsic differences within GCPs that impact on SHH-MB progression.

2018-02-22 | GSE110932 | GEO

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