Loss of Usp9x increases Wnt and Notch signaling in neural progenitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Nicholas Matigian
PROVIDER: E-MTAB-4150 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Constitutive activation of the anti-apoptotic NF-κB signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) that is characterized by adverse survival. Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 mutants in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-Catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-Catenin destruction complex was independent of CARMA1-BCL10-MALT1 (CBM) complex formation or constitutive NF-κB activation and promoted the stabilization of β-Catenin. Elevated β-Catenin expression was detected in cell lines and biopsies from ABC DLBCL that rely on chronic BCR signaling. Increased β-Catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-Catenin enhanced expression of immune suppressive IL-10 and repressed anti-tumoral CCL3, indicating that β-Catenin may induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-Catenin signaling by gain-of-function mutations in CARMA1 can augment WNT stimulation and is required for maintaining high expression of distinct NF-κB target genes and can thereby trigger cell intrinsic and extrinsic processes that promote DLBCL lymphomagenesis. CARMA1 mutants were expressed in BJAB, an NF-κB negative GCB DLBCL lymphoma cell line. Gene expression induced by GCB DLBCL derived CARMA1 L225LI mutant was compared with the empty vector (mock) control, CARMA1 WT, CARMA1 point mutant R35A and with CARMA1 double mutant R35A/L225LI.
2016-07-03 | E-GEOD-70025 | biostudies-arrayexpress
Project description:Asymmetric cell division results in two distinctly fated daughter cells to generate cellular diversity. A major molecular hallmark of an asymmetric division is the unequal partitioning of cell-fate determinant proteins. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which in turns drives migration and metastasis. Here, we report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell-fate determinants Numb (Notch antagonist) and β-catenin (canonical Wnt regulator) through the activity of a depalmitoylating enzyme, APT1. Using point mutants, we show specific palmitoylated residues on proteins, such as Numb, are required for asymmetric localization. Furthermore, by live-cell imaging, we show that reciprocal interactions between APT1 and CDC42 regulate the asymmetric localization of Numb and β-catenin to the plasma membrane. This in turn restricts Notch and Wnt transcriptional activity to one daughter cell. Moreover, we show altering APT1 expression changes the transcriptional signatures to those resembling that of Notch and β-catenin in MDA-MB-231 cells. We also show loss of APT1 depletes the population of CD44+/CD24lo/ALDH+ tumorigenic cells in colony formation assays. Together, the findings of this study demonstrate that palmitoylation, via APT1, is a major mechanism of asymmetric cell division regulating Notch and Wnt-associated protein dynamics, gene expression, and cellular functions.
2018-05-09 | GSE105486 | GEO
Project description:Sivakumar2011_WntSignalingPathway
The secreted protein Wnt activates the
heptahelical receptor Frizzled on nieghboring cells. Activation of
Frizzled causes the recruitment of additional membrane proteins
which in turn result in 1) the activation of the protein
Dishevelled via phosphorylation and 2) the activation of a
heterotrimeric G protein of unknown type. Activation of Dishevelled
results in the down-regulation of the Beta-Catenin destruction
complex which causes ubiquitination of Beta-Catenin and its
ultimate degradation via the proteasome. Inhibition of the
Beta-Catenin destruction complex yields a higher cytosolic
concentration of Beta-Catenin, which enters the nucleus, binds
various transcriptional regulatory molecules including the TCF/LEF
class of proteins, and results in the transcription of TCF/LEF
target genes. Activation of the heterotrimeric G-protein pathway in
turn activates Phospholipase C which in turn catalyzes the
catalysis of PI(4,5)P2 into DAG and IP3.
Reference:
The Wnt
signalling pathway.
You Wnt
some, you lose some: oncogenes in the Wnt signaling
pathway.
Wnt
signaling pathway.
This model is described in the article:
A systems biology approach
to model neural stem cell regulation by notch, shh, wnt, and
EGF signaling pathways.
Sivakumar KC, Dhanesh SB, Shobana S,
James J, Mundayoor S.
OMICS 2011 Oct; 15(10): 729-737
Abstract:
The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have
long been known to influence cell fate specification in the
developing nervous system. Here we attempted to evaluate the
contemporary knowledge about neural stem cell differentiation
promoted by various drug-based regulations through a systems
biology approach. Our model showed the phenomenon of
DAPT-mediated antagonism of Enhancer of split [E(spl)] genes
and enhancement of Shh target genes by a SAG agonist that were
effectively demonstrated computationally and were consistent
with experimental studies. However, in the case of model
simulation of Wnt and EGF pathways, the model network did not
supply any concurrent results with experimental data despite
the fact that drugs were added at the appropriate positions.
This paves insight into the potential of crosstalks between
pathways considered in our study. Therefore, we manually
developed a map of signaling crosstalk, which included the
species connected by representatives from Notch, Shh, Wnt, and
EGF pathways and highlighted the regulation of a single target
gene, Hes-1, based on drug-induced simulations. These
simulations provided results that matched with experimental
studies. Therefore, these signaling crosstalk models complement
as a tool toward the discovery of novel regulatory processes
involved in neural stem cell maintenance, proliferation, and
differentiation during mammalian central nervous system
development. To our knowledge, this is the first report of a
simple crosstalk map that highlights the differential
regulation of neural stem cell differentiation and underscores
the flow of positive and negative regulatory signals modulated
by drugs.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000397.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2011-11-02 | BIOMD0000000397 | BioModels
Project description:During vertebrate retinogenesis, the precise balance between retinoblast proliferation and differentiation is spatially and temporally regulated through a number of intrinsic factors and extrinsic signaling pathways. Moreover, there are complex gene regulatory network interactions between these intrinsic factors and extrinsic pathways, which ultimately function to determine when retinoblasts exit the cell cycle and terminally differentiate. We recently uncovered a cell non-autonomous role for the intrinsic HLH factor, Id2a, in regulating retinoblast proliferation and differentiation, with Id2a-deficient retinae containing an abundance of proliferative retinoblasts and an absence of terminally differentiated retinal neurons and glia. Here, we report that Id2a function is necessary and sufficient to limit Notch pathway activity during retinogenesis. Id2a-deficient retinae possess elevated levels of Notch pathway component gene expression, while retinae overexpressing id2a possess reduced expression of Notch pathway component genes. Attenuation of Notch signaling activity by DAPT or by morpholino knockdown of Notch1a is sufficient to rescue both the proliferative and differentiation defects in Id2a-deficient retinae. In addition to regulating Notch pathway activity, through an RNA-Seq and differential gene expression analysis of Id2a-deficient retinae, we identify a number of additional intrinsic and extrinsic regulatory pathway components whose expression is regulated by Id2a. These data highlight the integral role played by Id2a in the gene regulatory network governing the transition from retinoblast proliferation to terminal differentiation during vertebrate retinogenesis. Two biological replicates for both Id2aMM and Id2aMO samples
2012-08-27 | E-GEOD-38786 | biostudies-arrayexpress
Project description:β-Catenin is the major co-regulator of the Wnt signalling pathway. β-Catenin lysine 49 is post-translationally modified. The histone methyl transferase Ezh2 trimethylates β-catenin at lysine 49 and the acetyl transferase Cbp acetylates β-catenin at the same lysine. To determine the effects on gene expression embryonic stem cells containing either a Gfp tagged β-catenin wildtype (wt) or lysine 49 to alanine (K49A) loss of function mutation were analysed by micro array expression profiling. To determine the effects on gene expression in the pluripotent state two biological replicates of Gfp β-catenin wt and Gfp β-catenin K49A were analysed. The results showed that genes which affect pluripotency as well as differentiation were altered by β-catenin K49A mutation. To analyse the effects of gene expression during ES cell differentiation ES cells containing Gfp β-catenin wt or K49A were differentiated into mesodermal progenitors (mp) and neuronal progenitors (np). Two biological replicates were analysed by micro array expression profiling. Differentially expressed genes between Gfp β-catenin wt and K49A during differentiation were observed. Mesodermal marker genes like t-brachyury and cdx2 were not upregulated in mesodermal differentiation of Gfp β-catenin K49A Es cells.
2017-03-21 | E-MTAB-5523 | biostudies-arrayexpress
Project description:The ventricular wall of the heart is composed of trabeculated and compactlayers, which are separated by yet unknown processes during embryonic development. Notch signaling plays important roles in cardiac development. Mutations in Notch signaling components are related to human congenital heart diseases Two homologues, Numb and Numblike (Numbl), are expressed in mammals, which also act as inhibitors of Notch signaling. Here we investigate the role of Notch2 and Numb/Numblike during myocardial trabeculation and compaction. The aim of the experiment is to analyze whether Numb/Numblike are involved in inhibition of Notch activity in the developing heart. Since Overexpression of N2ICD phenocoped Numb/Numblike mutants, we performed micoarray using total RNA from aMHC-Cre-mediated overexpression of N2ICD.
2013-04-09 | E-MEXP-3661 | biostudies-arrayexpress
Project description:The ventricular wall of the heart is composed of trabeculated and compactlayers, which are separated by yet unknown processes during embryonic development. Notch signaling plays important roles in cardiac development. Mutations in Notch signaling components are related to human congenital heart diseases Two homologues, Numb and Numblike (Numbl), are expressed in mammals, which also act as inhibitors of Notch signaling Here we investigate the role of Notch2 and Numb/Numblike during myocardial trabeculation and compaction. The aim of the experiment is to analyze whether Numb/Numblike are involved in inhibition of Notch activity in the developing heart.
2013-01-17 | E-MEXP-3490 | biostudies-arrayexpress
Project description:Appropriate neural initiation of the pluripotent stem cells in the early embryos is critical for the development of the central nervous system. This process is regulated by the coordination of extrinsic signals and intrinsic programs. However, how the coordination is achieved to ensure proper neural fate commitment is largely unknown. Here, taking advantage of genome-wide ChIP-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) analyses, we demonstrate that the transcriptional factor Pou3f1 is an upstream activator of neural-promoting genes, and it is able to repress neural-inhibitory signals as well. Further studies revealed that Pou3f1 could directly bind neural lineage genes like Sox2 and downstream targets of neural inhibition signaling such as BMP and Wnt. Our results thus identify Pou3f1 as a critical dual-regulator of the intrinsic transcription factors and the extrinsic cellular signals during neural fate commitment. ChIP-seq assay was ultilized to characterize the targets of Pou3f1 on ESC differentiation day 2.
2015-11-23 | E-GEOD-69778 | biostudies-arrayexpress
Project description:During vertebrate retinogenesis, the precise balance between retinoblast proliferation and differentiation is spatially and temporally regulated through a number of intrinsic factors and extrinsic signaling pathways. Moreover, there are complex gene regulatory network interactions between these intrinsic factors and extrinsic pathways, which ultimately function to determine when retinoblasts exit the cell cycle and terminally differentiate. We recently uncovered a cell non-autonomous role for the intrinsic HLH factor, Id2a, in regulating retinoblast proliferation and differentiation, with Id2a-deficient retinae containing an abundance of proliferative retinoblasts and an absence of terminally differentiated retinal neurons and glia. Here, we report that Id2a function is necessary and sufficient to limit Notch pathway activity during retinogenesis. Id2a-deficient retinae possess elevated levels of Notch pathway component gene expression, while retinae overexpressing id2a possess reduced expression of Notch pathway component genes. Attenuation of Notch signaling activity by DAPT or by morpholino knockdown of Notch1a is sufficient to rescue both the proliferative and differentiation defects in Id2a-deficient retinae. In addition to regulating Notch pathway activity, through an RNA-Seq and differential gene expression analysis of Id2a-deficient retinae, we identify a number of additional intrinsic and extrinsic regulatory pathway components whose expression is regulated by Id2a. These data highlight the integral role played by Id2a in the gene regulatory network governing the transition from retinoblast proliferation to terminal differentiation during vertebrate retinogenesis.
2012-08-27 | GSE38786 | GEO
Project description:Decoding heterogeneity of pluripotent stem cell (PSC)-derived neural progeny is fundamental for revealing the origin of diverse progenitors, for defining their lineages, and for identifying fate determinants driving transition through distinct potencies. Here we prospectively isolated consecutively appearing PSC-derived primary progenitors based on their Notch activation state. We first isolate early neuroepithelial cells and show their broad Notch-dependent developmental and proliferative potential. Neuroepithelial cells further yield successive Notch-dependent functional primary progenitors, from early and mid neurogenic radial glia and their derived basal progenitors, to gliogenic radial glia and adult-like neural progenitors, together recapitulating hallmarks of neural stem cell (NSC) ontogeny. Gene expression profiling reveals dynamic stage specific transcriptional patterns that may link development of distinct progenitor identities through Notch activation. Our observations provide a platform for characterization and manipulation of distinct progenitor cell types amenable for developing streamlined neural lineage specification paradigms for modeling development in health and disease. Human embryonic stem cells (hESCs) H9 were differentiated into 5 distinct populations of neural precursor cells (NPCs) over a time course of 200 days. Each neural precursor populations was then sorted for HES5 expression based on a GFP-HES5 reporter. Both the HES5 positive and HES5 negative populations were then subjected to microarray profiling in singlicate, as well as the hESCs using GeneChipPrimeView Human Gene Expression Array
2015-02-18 | E-GEOD-65369 | biostudies-arrayexpress