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Specific functions for ERK/MAPK signaling during PNS development

ABSTRACT: We have established functions of the stimulus dependent MAPKs, ERK1/2 and ERK5 in DRG, motor neuron, and Schwann cell development. Surprisingly, many aspects of early DRG and motor neuron development were found to be ERK1/2 independent and Erk5 deletion had no obvious effect on embryonic PNS. In contrast, Erk1/2 deletion in developing neural crest resulted in peripheral nerves that were devoid of Schwann cell progenitors, and deletion of Erk1/2 in Schwann cell precursors caused disrupted differentiation and marked hypomyelination of axons. The Schwann cell phenotypes are similar to those reported in neuregulin-1 and ErbB mutant mice and neuregulin effects could not be elicited in glial precursors lacking Erk1/2. ERK/MAPK regulation of myelination was specific to Schwann cells, as deletion in oligodendrocyte precursors did not impair myelin formation, but reduced precursor proliferation. Our data suggest a tight linkage between developmental functions of ERK/MAPK signaling and biological actions of specific RTK-activating factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE24730 | GEO | 2010/10/16

SECONDARY ACCESSION(S): PRJNA132351

REPOSITORIES: GEO

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Specific functions for ERK/MAPK signaling during PNS development

Project description:We have established functions of the stimulus dependent MAPKs, ERK1/2 and ERK5 in DRG, motor neuron, and Schwann cell development. Surprisingly, many aspects of early DRG and motor neuron development were found to be ERK1/2 independent and Erk5 deletion had no obvious effect on embryonic PNS. In contrast, Erk1/2 deletion in developing neural crest resulted in peripheral nerves that were devoid of Schwann cell progenitors, and deletion of Erk1/2 in Schwann cell precursors caused disrupted differentiation and marked hypomyelination of axons. The Schwann cell phenotypes are similar to those reported in neuregulin-1 and ErbB mutant mice and neuregulin effects could not be elicited in glial precursors lacking Erk1/2. ERK/MAPK regulation of myelination was specific to Schwann cells, as deletion in oligodendrocyte precursors did not impair myelin formation, but reduced precursor proliferation. Our data suggest a tight linkage between developmental functions of ERK/MAPK signaling and biological actions of specific RTK-activating factors. Microarray analysis on RNA extracts derived from E12.5 Erk1/2CKO(Wnt1) and wildtype DRGs

2010-10-16 | E-GEOD-24730 | biostudies-arrayexpress

11q deletion or ALK activity curbs DLG2 expression to maintain an undifferentiated state in neuroblastoma.

Project description:High-risk 11q deleted neuroblastomas (NBs) typically display an undifferentiated/poorly differentiated morphology. NB is thought to develop from Schwann cell precursors (SCPs) and un-differentiated neural crest derived cells (NCC). It is therefore vital to understand the mechanisms involved in the block of differentiation. We showed that an important and novel role for oncogenic ALK-ERK1/2-SP1 signaling may be the maintenance of an undifferentiated state of transformed NC-derived progenitors that is achieved by repression of DLG2, a tumor suppressor in NB. DLG2 is expressed in the ‘bridge signature’ that represents the transcriptional transition state when neural crest cells or Schwann Cell Precursors (SCP) become chromaffin cells of the adrenal gland. The importance of SP1 and DLG2 in this process is highlighted by our findings that restoring DLG2 expression spontaneously drives NB differentiation. Further, genetic analysis of high-risk 11q deletion NB patient identified genetic lesions in the DLG2 gene, Our data also suggest that further exploration of other ‘bridge genes’ may help to better understand the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to NB.

2020-11-25 | PXD017946 | Pride

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Project description:Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal and tissue-restricted deletions have profound effects on erythroid development, cardiac function and neurogenesis. In addition, depletion of ERK5 is anti-inflammatory and anti-tumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no anti-inflammatory or anti-proliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains (BRDs), conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a non-catalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity, and delineate which can be pharmacologically targeted.

2016-09-09 | GSE86577 | GEO

Single-cell RNA-seq reveals the difference between Schwann cells in dorsal root ganglion and sciatic nerve

Project description:Schwann cells are important glial cells in peripheral nervous system. In this study, we performed single cell RNA-sequencing (scRNA-seq) analysis of Schwann cells exist in both dorsal root ganglion(DRG) and sciatic nerve.We categorized DRG and sciatic nerve Schwann cells into different subtypes,and found common subtypes and different subtypes.In addition, we discovered the proliferation and migration ability of Schwann cells were distinct in different tissues.Our current study revealed the distinctive characteristics of Schwann cells in DRG and sciatic nerve.

2023-03-26 | GSE147615 | GEO

Expression data from mesothelial (LP9) and mesothelioma cells (HMESO) inhibited for extracellular-regulated kinase (ERK) 1, 2, or 5

Project description:Extracellular-regulated kinases (ERK1/2 and 5) are known to play important roles in growth and drug resistance of various cancers. Here we show roles of inhibition of ERK1, ERK2, or ERK5 on gene expression profiles of epithelioid malignant mesothelioma (MM) cells (HMESO).

2010-05-08 | GSE21750 | GEO

Loss of Spry1 reduces growth of BRAFV600E-mutant cutaneous melanoma and improves response to targeted therapy

Project description:Mitogen-activated protein kinase (MAPK) pathway activation is a central step in BRAFV600E-mutant cutaneous melanoma (CM) pathogenesis. In the last years, Spry1 has been frequently described as an upstream regulator of MAPK signaling pathway. However, its specific role in BRAFV600E-mutant CM is still poorly defined. Here, we report that Spry1 knockdown (Spry1KO) in three BRAFV600E-mutant CM cell lines markedly induced cell cycle arrest and apoptosis, repressed cell proliferation in vitro, and impaired tumor growth in vivo. Furthermore, our findings indicated that Spry1KO reduced the expression of several EMT-markers, such as MMP-2 both in vitro and in vivo. These effects were associated with a sustained and deleterious phosphorylation of ERK1/2. In addition, p38 activation along with an increase in basal ROS levels were found in Spry1KO clones compared to parental CM cell lines, suggesting that BRAFV600E-mutant CM may restrain the activity of Spry1 to avoid oncogenic stress and to enable tumor growth. Consistent with this hypothesis, treatment with the BRAF inhibitor (BRAFi) vemurafenib down-regulated Spry1 levels in parental CM cell lines, indicating that Spry1 expression is sustained by MAPK/ERK signaling pathway in a positive feedback loop that safeguards cells from the potentially toxic effects of ERK1/2 hyperactivation. Disruption of this feedback loop rendered Spry1KO cells more susceptible to apoptosis and markedly improved response to BRAFi both in vitro and in vivo, as a consequence of the detrimental effect of ERK1/2 hyperactivation observed upon Spry1 abrogation. Therefore, targeting Spry1 might offer a treatment strategy for BRAFV600E-mutant CM by inducing the toxic effects of ERK-mediated signaling.

2020-05-26 | E-MTAB-7886 | biostudies-arrayexpress

Erk1/2 mediated negative feedback regulation is essential for postnatal intestinal development and homeostasis

Project description:Objective: Homeostasis of intestinal stem cells (ISCs) is maintained by external niche signals and complicated intrinsic signaling networks. Mitogen-activated protein kinase (MAPK) cascades play pivotal roles in stem cell self-renewal and differentiation, but the functions and underlying molecular mechanisms are not fully understood. Design: We performed studies with mice deletion of Erk1/2 genes in intestinal epithelial cells at embryonic stages or a control mice. Intestinal tissues were collected and analyzed by histology, gene expression profiling, immunohistochemistry, immunfluorescence, western blotting and organoid culture. Organoids were treated with specific inhibitors for Ras or Akt activity. Mice were treated by intraperitoneal injection of rapamycin to inhibit mTOR signaling. Results: We found that deletion of Erk1/2 genes resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 strongly impaired secretory cell differentiation and enterocyte maturation with aberrant Wnt signaling activation. Erk1/2 depletion resulted in loss of feedback regulation leading to Ras/Raf cascade activation. Ras then transactivated Akt activity to stimulate mTOR and phosphorylate β-catenin on Ser552. Suppression of Ras or Akt activity through specific inhibitors significantly repressed Akt downstream signaling and restored cell proliferation and differentiation phenotypes ex vivo. Moreover, inhibition of mTOR signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged mutant mouse life span. Conclusions Our study demonstrates an unexplored critical role of ERK/MAPK pathway negative feedback regulation of Akt/mTOR in intestine development and homeostasis, suggesting a complicated regulatory network in ISC function.

2020-08-10 | GSE134249 | GEO

Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

Project description:The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes (T2D) following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that icv FGF1 injection induces signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family in the hypothalamus, and that this activation persists for at least 24h. Further, we show that in diabetic Lepob/ob mice, this prolonged response is required for the sustained antidiabetic action of FGF1, since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, elicits transient but not sustained glucose lowering. These data implicate sustained hypothalamic MAPK/ERK signaling in the mechanism underlying diabetes remission induced by icv FGF1.

2021-07-12 | GSE179918 | GEO

Gene expression profile in DRG neurons over-expressing NRG1 type III intracellular domain

Project description:In DRG neurons NRG1 type III intacellular domain (ICD) moves to the nucleus upon contact with Schwann cells. We aimed to investigate genes up/down regulated by ICD. We analyzed total RNA from DRG neurons over-expressing ICD comparing it to RNA from wild-type DRG neurons and RNA from DRG neurons over-expressing EGFP. We used 4 biological replicates and two technical replicates for each condition.

2014-09-26 | E-GEOD-61784 | biostudies-arrayexpress

RNA-seq data of BRAF wild-type and BRAF mutant tumor cells treated with the ERK inhibitor GDC-0994

Project description:BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. Our date showed that the expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells.

2024-04-15 | GSE264049 | GEO

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