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GSE41747
Mus musculus, Homo sapiens
66 Downloadable Samples
Description
Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials.
Publication Title
MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 19 Downloadable Samples
Description
During embryogenesis, many key transcription factors are used repeatedly, achieving different outcomes depending on cell type and developmental stage. The epigenetic modification of the genome functions as a memory of a cells developmental history, and it has been proposed that such modification shapes the cellular response to transcription factors. To investigate the role of DNA methylation in the response to transcription factor Gata4, we examined expression profiles of Dnmt3a-/-Dnmt3b-/- ES cell-derived mesoderm cells cultured for 4 days with or without Gata4 activation, as well as the wild-type counterparts, using Affymetrix microarrays.
Publication Title
DNA methylation restricts lineage-specific functions of transcription factor Gata4 during embryonic stem cell differentiation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 104 Downloadable Samples
Description
The adult mammalian brain is composed of distinct regions that have specialized roles. The BF/POA regions are thought to have an important role in the regulation of sleep/wake behavior. However, genetic markers of the responsible cells for the regulation of sleep/wake behavior are largely unknown. To identify the molecular markers of the BF/POA regions, we sampled the BF/POA regions and compared gene expression in the BF/POA regions with those of other brain regions which we previously reported in the BrainStars (B*) project, in which we sampled ~50 small brain regions, including sensory centers and centers for motion, time, memory, fear, and feeding.
Publication Title
Muscarinic Acetylcholine Receptors Chrm1 and Chrm3 Are Essential for REM Sleep.
Sample Metadata Fields
Sex, Specimen part
View Samples