Cell autonomous requirement of Neurofibrimin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE147605 | GEO | 2021/01/04
REPOSITORIES: GEO
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Project description:Background Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in Neurofibromin (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients’ mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy is mostly unknown. Methods To dissect the function of Nf1 in muscle, we created muscle-specific knockout mouse models for Nf1, inactivating Nf1 in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analyzed during pre-and postnatal myogenesis and muscle growth. Results Nf1Lbx1 and Nf1Myf5 animals showed only mild defects in prenatal myogenesis. Nf1Lbx1 animals were perinatally lethal, while Nf1Myf5 animals survived up to approx. 25 weeks. Nf1Myf5 animals showed decreased postnatal growth, reduced muscle size, and fast fiber atrophy. Proteome and transcriptome analysis of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. Real-time respirometry demonstrated enhanced oxidative metabolism in Nf1Myf5 muscles concomitant to a fiber type shift from type 2B to type 2A and type 1. Nf1Myf5 muscles showed hallmarks of mild oxidative stress and increased activation of AMPK indicating an energy deficit, increased expression of atrogenes and decreased activation of mTORC1. Proteome and transcriptome analysis indicated that oxidative fibers mainly relied on fatty acid catabolism. Inline, Nf1Myf5 animals showed a drastic reduction of white, but not brown, adipose tissue. Conclusions Our results demonstrate a cell-autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle leads to cross-tissue communication and mobilization of lipid reserves.
2020-10-26 | PXD017958 | Pride
Project description: Not available
| S-EPMC7749575 | biostudies-literature
Project description:Cell autonomous requirement of Neurofibrimin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis
| PRJNA615679 | ENA
Project description:Purpose: To study Nf1 regulated pathways in controlling juvenile satellite cells quiescence induction. Methods: We sequenced total mRNAs isolated from juvenile satellite cells FACS sorted from postnatal day 7 Control (Nf1flox/+ Myf5Cre+) and KO (Nf1flox/flox Myf5Cre+) mouse hindlimb skeletal muscle. Results: Our study suggests that Nf1 is required for maintaining the balance between quiescence induction and amplification / differentiation in the postnatal MP pool. Conclusions: The tumor suppressor Nf1 maintains the myogenic progenitor (MP) pool during postnatal muscle development.
2021-09-25 | GSE159021 | GEO
Project description:One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary café-au-lait macules where dysregulation of melanocyte development, proliferation and differentiation is considered to play a key etiopathogenic role. To gain better insight in the possible role of the tumor suppressor gene NF1, a transcriptomic microarray analysis was performed on human NF1 heterozygous (NF1+/-) melanocytes of a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient, both cultured from normally pigmented and hyperpigmented lesional café-au-lait skin. Out of 13,850 unique genes, a total of 137 had a significant twofold or more up- (72) or down-regulated (65) expression in NF1+/- melanocytes compared to NF1+/+ melanocytes (genotype effect). Considering possible intrinsic genetic variation in lesional skin, melanocytes showed a total of 51 genes having a significant twofold or more up- (37) or down-regulated (14) expression when they were cultured from hyperpigmentary café-au-lait skin compared to normally pigmented skin (lesional skin type effect). NF1+/- café-au-lait skin melanocytes showed 468 genes with a significant two-fold or more up- (183) or down-regulated (285) expression going beyond the sum of the separate main effects (interaction). Detailed analysis enabled the identification of several modulated genes in NF1+/- (café-au-lait skin) melanocytes, mainly involved in controlling cell proliferation and cell maintenance, in cell adhesion and, surprisingly, in the immune response. An interesting finding was that a high number of transcription factor genes were differentially modulated, among which a specific subset - important in melanocyte-lineage development - showed downregulation in a transcriptional cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene.
2005-02-05 | E-MEXP-258 | biostudies-arrayexpress
Project description:Analysis of the effect of NF1 second hit mutation to the reading of the whole human genome by comparing the gene expression profiles of neurofibroma derived Schwann cell cultures representing two different NF1 genotypes (NF1+/- and NF1-/-).
2016-12-22 | GSE32029 | GEO
Project description:Schwann cells and macrophages were dissociated from normal DRGs and 1- and 7-month-old neurofibroma. Schwann cells from neurofibroma have Nf1-/- phenotypes. All macrophages have Nf1+/+ phenotypes. We used microarrays (Affymetrix MoGene 2.0 ST GeneChip) to detect transcriptomal changes between 7-month-old neurofibroma Schwann cells (or macrophages) versus 1-month-old wild-type (or neurofibroma) Schwann cells (or macrophages). Expression data of three sets of cells: (1)Schwann cells and macrophages from 1-month-old wild-type mouse dorsal root ganglia, (2) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 1-month-old neurofibroma, (3) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 7-month-old neurofibroma We chopped mouse DRG/neurofibromas into 1-3 mm^3 pieces and plated them in dissociation medium containing 20mL L-15 (Mediatech), 0.5 mg/mL collagenase type 1 (Worthington; Lakewood, NJ), and 2.5 mg/mL dispase protease type II (Cambrex; East Rutherford, NJ) at 37°C for 4-6 hours with shaking. The dissociation reaction was stopped by adding DMEM +10%FBS. Undigested DRG/tumors were excluded by 100µM cell strainer. Cells were collected by centrifugation. For each microarrays (Schwann cell, macrophage), Affymetrix GeneChip Command Console (v4.0.0) was used to create .chp files. All the probe sets on Affymetrix Mouse Gene 2.0 ST array (Mogene-2_0-st-v1.na33.2.mm10) were summarized by Affymetix Expression Console program using robust multi-chip average (RMA) method . After preprocessing steps, data from two batches were combined and their batch effects were corrected using ComBat method Please note that [1] all MP samples are Nf1+/+ (no mutation on Nf1 gene) and the only difference is their ages (1month, 7month) and [2] the 'nf1' in sample title reperesents "neurofibroma type1 disease", not "Nf1 gene".
2017-05-01 | E-GEOD-78901 | biostudies-arrayexpress
Project description:To allow accute charaterization of NF1 locus constitutional microdeletion in 70 NF1 patients, a custom array CGH was developped. Goal was to obtain genomic rearrangements fine characterization in order to perform genotype-phenotype correlation in NF1 microdeleted patients. To serve as a reference group in our genotype-phenotype correlation study in NF1 microdeletion patients, non-deleted NF1 patients (i.e. patients with an intragenic NF1 mutation) were also selected from our database. A total of 389 NF1 patients were included in the reference group of non-deleted patients. Multiple logistic regression was performed to test the association of each clinical feature individually with the type of constitutional NF1 mutation (intragenic mutation vs. microdeletion). The phenotypic traits of the 389 reference patients are available in the "GSE19730_control_patient_characteristics.txt" supplementary file on the Series record. NF1 locus microdeletions characterization vs reference sample (pool of six normal control DNAs)
2010-05-26 | E-GEOD-19730 | biostudies-arrayexpress
Project description:Neurofibromatosis Type 1 (NF1) is a tumor predisposition syndrome with pleiotropic somatic manifestations, including formation of bone pseudarthrosis after fracture. The pathogenesis of NF1 pseudarthroses remains unclear, though defects in osteogenesis have been posited. Here, we applied time-series single-cell RNA-sequencing (scRNAseq) to patient-matched control and pseudarthrosis-derived primary bone mesenchymal stromal cells (MSCs). We show that osteogenesis occurs in NF1-/- MSCs. In contrast, expression of genetic pathways associated with skeletal mineralization were reduced in NF1-/- cells compared to co-cultured NF1+/- fracture-derived cells.
2022-12-13 | GSE196652 | GEO
Project description:Genomic rearrangements may cause both Mendelian and complex disorders. Currently, several major mechanisms causing genomic rearrangements have been proposed such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR). However, to what extent these mechanisms contribute to gene-specific pathogenic copy-number changes (CNCs) remains understudied. Furthermore, only few studies resolved these pathogenic alterations at nucleotide-level resolution. Accordingly, our aim is to explore which mechanisms contribute to a large, unique set of locus-specific non-recurrent genomic rearrangements causing the genetic neurocutaneous disorder neurofibromatosis type 1 (NF1). Through breakpoint-spanning PCR as well as array Comparative Genomic Hybridization (aCGH), we have identified the breakpoints and characterized the likely rearrangement mechanism of the NF1 intragenic CNCs in 78 unrelated patients. Unlike the most typical recurrent rearrangements mediated by flanking low copy repeats (LCRs), NF1 intragenic CNCs have diverse breakpoint locations, and are characterized by different rearrangement mechanisms. We propose the DNA replication-based mechanisms comprising FoSTeS/MMBIR and serial replication stalling to be the predominant mechanism leading to NF1 intragenic CNCs. In addition to the loop of a 197-bp palindrome located in intron 40, four Alu elements located in intron 1, 2, 3 and 50 were also identified as significant intragenic rearrangement hotspots within the NF1 gene. However, no clear genotype-phenotype correlations could be identified among the NF1 patients carrying NF1 intragenic CNCs. Patient DNA samples with non-overlapping CNCs, as estimated by MLPA, were labeled with Cy3 and Cy5 fluorophores respectively, and hybridized onto the microarray. Alternatively, patient DNA was hybridized versus unrelated individual blood DNA. No hybridizations using biological replicates were performed. In total 6 samples were included. Please note that our experimental setup included a hybridization in which two DNA samples with non-overlapping deletions, from two NF1 patients, were hybridized in one experiment (sample codes: 1253 and 1403). In this specific case, assigning test or reference function to the samples was a matter of arbitrary choice. However, if needed, sample 1253 can be denoted as test, and sample 1403 can be denoted as reference in this experiment.
2015-07-30 | E-GEOD-64869 | biostudies-arrayexpress